{"gene":"PF3D7_1239500","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2007,"finding":"PfGyrB (PF3D7_1239500) displays strong intrinsic ATPase activity and undergoes ATP-independent dimerization, unlike E. coli GyrB. The PfgyrB gene complemented an E. coli gyrase temperature-sensitive strain, and together with the N-terminal domain of PfGyrA it reconstituted DNA cleavage activity, confirming GyrB is a functional gyrase subunit.","method":"Recombinant protein expression, in vitro ATPase assay, E. coli complementation, DNA cleavage assay","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution, complementation, and multiple orthogonal functional assays in a single study","pmids":["17220464"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"PfGyrB (PF3D7_1239500) ATPase activity is inhibited by novobiocin, and novobiocin treatment of parasites in culture reduces the apicoplast/nuclear DNA ratio, indicating GyrB is involved in apicoplast DNA replication. Antibodies against recombinant PfGyrB confirmed the protein's presence in parasite lysates. Molecular modeling showed conservation of the ATPase domain fold with E. coli GyrB and the presence of a unique disordered loop adjacent to the ATPase domain.","method":"In vitro ATPase inhibition assay, parasite culture inhibition, apicoplast/nuclear DNA ratio measurement, immunoblotting with anti-recombinant PfGyrB antibodies, molecular modeling","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (biochemical inhibition, DNA quantification, immunodetection) in a single study linking GyrB activity to apicoplast DNA replication","pmids":["17499371"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"The ATP-binding domain of P. vivax GyrB (ortholog of PF3D7_1239500) expressed as a 43 kDa recombinant polypeptide shows intrinsic ATPase activity (Km = 0.27 mM, kcat = 0.051 s−1) that is sensitive to the bacterial gyrase inhibitor coumermycin.","method":"Recombinant protein expression, in vitro ATPase kinetics assay, coumermycin inhibition assay","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro enzymatic characterization but single lab, single species (P. vivax), no replication","pmids":["15694492"],"is_preprint":false,"attribution":[{"species":"Plasmodium vivax","strain":""}]},{"year":2021,"finding":"PfGyrB (PF3D7_1239500) was reconstituted with E. coli GyrA to form a functional hybrid gyrase enzyme. The compound purpurogallin (PPG) preferentially inhibits this hybrid enzyme over E. coli gyrase by disrupting DNA binding to the hybrid complex and consequently reducing DNA-induced ATPase activity of PfGyrB; binding studies showed PPG has higher affinity for PfGyrB than for E. coli GyrB.","method":"Hybrid enzyme reconstitution (PfGyrB + E. coli GyrA), supercoiling activity assay, ATPase assay, binding affinity measurement","journal":"Antimicrobial agents and chemotherapy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzyme reconstitution, mechanistic dissection (DNA binding disruption → ATPase reduction), binding studies, multiple orthogonal methods in single study","pmids":["34339271"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"finding":"UNC8153 and Fexofenadine hydrochloride were identified as inhibitors of PfGyrB (PF3D7_1239500) ATPase activity in vitro and showed time-dependent antiplasmodial activity in parasite growth assays, including against an artemisinin-resistant C580Y strain; UNC8153 showed ~25-fold greater antiplasmodial activity than novobiocin at 96 h.","method":"Virtual screening, biochemical ATPase inhibition assay, parasite growth inhibition assay, morphological analysis","journal":"Chemical biology & drug design","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro ATPase and parasite inhibition assays combined, but single lab, no mechanistic follow-up on GyrB-specific mode of action beyond ATPase inhibition","pmids":["42482438"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfGyrB (PF3D7_1239500) is a nuclear-encoded, apicoplast-targeted DNA gyrase B subunit that possesses intrinsic ATPase activity (with unique ATP-independent dimerization not seen in bacterial GyrB), forms a functional heterotetramer with GyrA to introduce negative supercoils into DNA, is required for apicoplast DNA replication, and is inhibited by bacterial gyrase inhibitors (novobiocin, coumermycin) as well as by novel compounds (e.g. purpurogallin) that disrupt its DNA-binding and DNA-stimulated ATPase activities."},"narrative":{"mechanistic_narrative":"GyrB (PF3D7_1239500) is a functional DNA gyrase B subunit of Plasmodium falciparum that supplies the ATPase activity of an apicoplast-localized gyrase and is required for apicoplast DNA replication [PMID:17220464, PMID:17499371]. Recombinant PfGyrB displays strong intrinsic ATPase activity, complements an E. coli gyrase temperature-sensitive strain, and reconstitutes DNA cleavage activity together with the N-terminal domain of PfGyrA, confirming it acts as a genuine gyrase subunit; distinctively, it undergoes ATP-independent dimerization not seen in E. coli GyrB [PMID:17220464]. Its ATPase activity is inhibited by the bacterial gyrase inhibitor novobiocin, and novobiocin treatment of cultured parasites lowers the apicoplast/nuclear DNA ratio, tying GyrB function to apicoplast genome maintenance [PMID:17499371]. The enzyme is amenable to hybrid reconstitution with E. coli GyrA, in which purpurogallin preferentially inhibits the hybrid by disrupting DNA binding and thereby the DNA-stimulated ATPase activity of PfGyrB [PMID:34339271]. GyrB's druggable ATPase activity makes it an antimalarial target, with additional inhibitors (UNC8153, fexofenadine) showing antiplasmodial activity including against an artemisinin-resistant strain [PMID:42482438]. Beyond these enzymatic and pharmacological characterizations, no further mechanistic detail (e.g., in-parasite genetic knockout or structural determination) has been characterized in the available corpus.","teleology":[{"year":2005,"claim":"Establishing that the Plasmodium GyrB ATP-binding domain is an active, drug-sensitive ATPase addressed whether the parasite encodes a genuine gyrase B enzymatic module.","evidence":"Recombinant 43 kDa ATP-binding domain of P. vivax GyrB (ortholog of PF3D7_1239500) characterized by in vitro ATPase kinetics and coumermycin inhibition","pmids":["15694492"],"confidence":"Medium","gaps":["Shown for the P. vivax ortholog, not directly for PF3D7_1239500","Only the isolated ATP-binding domain, not full-length or holoenzyme","No demonstration of gyrase supercoiling or GyrA partnership"],"attribution":[{"species":"Plasmodium vivax","strain":""}]},{"year":2007,"claim":"Direct enzymatic reconstitution and complementation established PfGyrB as a bona fide gyrase subunit and revealed a parasite-specific ATP-independent dimerization property.","evidence":"Recombinant PfGyrB ATPase assay, E. coli gyrase ts-strain complementation, and DNA cleavage reconstitution with the N-terminal domain of PfGyrA","pmids":["17220464"],"confidence":"High","gaps":["Full supercoiling reconstitution with native PfGyrA not shown","Functional significance of ATP-independent dimerization unresolved","No in-parasite genetic evidence of essentiality"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"claim":"Linking GyrB inhibition to a fall in the apicoplast/nuclear DNA ratio connected the enzyme's biochemical activity to its cellular role in apicoplast DNA replication.","evidence":"In vitro novobiocin ATPase inhibition, apicoplast/nuclear DNA ratio measurement in novobiocin-treated cultures, anti-PfGyrB immunoblotting, and molecular modeling of the ATPase domain","pmids":["17499371"],"confidence":"High","gaps":["Apicoplast DNA effect is pharmacological, not from a GyrB-specific genetic perturbation","Subcellular localization inferred from function/modeling rather than imaging","Role of the unique disordered loop not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"A hybrid PfGyrB/E. coli GyrA enzyme provided a tractable system to dissect a parasite-selective inhibitor's mechanism, showing inhibition proceeds through disrupted DNA binding and reduced DNA-stimulated ATPase activity.","evidence":"Hybrid enzyme reconstitution, supercoiling and ATPase assays, and binding-affinity measurements with purpurogallin","pmids":["34339271"],"confidence":"High","gaps":["Uses E. coli GyrA rather than native PfGyrA","Selectivity and efficacy against live parasites via this mechanism not established here","No structural model of the PfGyrB-inhibitor interaction"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"claim":"Screening-derived ATPase inhibitors with antiplasmodial activity, including against an artemisinin-resistant strain, extended GyrB's status as an actionable antimalarial drug target.","evidence":"Virtual screening, biochemical ATPase inhibition, and parasite growth/morphology assays with UNC8153 and fexofenadine against wild-type and C580Y strains","pmids":["42482438"],"confidence":"Medium","gaps":["No mechanistic follow-up beyond ATPase inhibition","On-target engagement in parasites not confirmed","Selectivity over host targets not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether PfGyrB is genetically essential in the parasite and how the holoenzyme is structurally organized and targeted to the apicoplast remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No conditional knockout/knockdown of PF3D7_1239500 in the corpus","No experimental structure of PfGyrB or the PfGyrA/PfGyrB holoenzyme","Apicoplast import signal and trafficking not directly characterized"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["DNA gyrase heterotetramer (with PfGyrA)","Hybrid gyrase reconstituted with E. coli GyrA"],"partners":["PFGYRA (N-TERMINAL DOMAIN, RECONSTITUTION PARTNER)","E. COLI GYRA (HYBRID ENZYME PARTNER)"],"other_free_text":["Displays parasite-specific ATP-independent dimerization not seen in E. coli GyrB [#0]","Contains a unique disordered loop adjacent to the ATPase domain by molecular modeling [#1]","Inhibited by bacterial gyrase inhibitors novobiocin and coumermycin [#1, #2]","Inhibited by purpurogallin via disruption of DNA binding and DNA-stimulated ATPase activity [#3]","Inhibited by UNC8153 and fexofenadine, with antiplasmodial activity including against artemisinin-resistant C580Y parasites [#4]","Findings at idx #2 derive from the P. vivax ortholog, not PF3D7_1239500 directly"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"3011062","id":"PMC_3011062","title":"Purification and characterization of Plasmodium berghei DNA topoisomerases I and II: drug action, inhibition of decatenation and relaxation, and stimulation of DNA cleavage.","date":"1986","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3011062","citation_count":77,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"3088783","id":"PMC_3088783","title":"Rapid repeated DNA replication during microgametogenesis and DNA synthesis in young zygotes of Plasmodium berghei.","date":"1986","source":"Transactions of the Royal Society of Tropical Medicine and Hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/3088783","citation_count":61,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17499371","id":"PMC_17499371","title":"Nuclear gyrB encodes a functional subunit of the Plasmodium falciparum gyrase that is involved in apicoplast DNA replication.","date":"2007","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/17499371","citation_count":58,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GyrB","PfGyrB"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17220464","id":"PMC_17220464","title":"Molecular cloning of apicoplast-targeted Plasmodium falciparum DNA gyrase genes: unique intrinsic ATPase activity and ATP-independent dimerization of PfGyrB subunit.","date":"2007","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/17220464","citation_count":57,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GyrB","DNA","PfGyrB"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"4971014","id":"PMC_4971014","title":"DNA, RNA , and protein synthesis in erythrocytic forms of Plasmodium knowlesi.","date":"1968","source":"The American journal of tropical medicine and hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/4971014","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15948708","id":"PMC_15948708","title":"DNA-[adenine] methylation in lower eukaryotes.","date":"2005","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/15948708","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2892060","id":"PMC_2892060","title":"From Laveran's discovery to DNA probes: new trends in diagnosis of malaria.","date":"1987","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/2892060","citation_count":31,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15694492","id":"PMC_15694492","title":"Expression and characterization of the ATP-binding domain of a malarial Plasmodium vivax gene homologous to the B-subunit of the bacterial topoisomerase DNA gyrase.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15694492","citation_count":19,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GyrB","DNA","PvGyrB"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34339271","id":"PMC_34339271","title":"Inhibitory Compounds Targeting Plasmodium falciparum Gyrase B.","date":"2021","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/34339271","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GyrB"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42337902","id":"PMC_42337902","title":"Mechanistic Insights into the Inhibition of Plasmodium falciparum DNA Gyrase A by Withanolide Derivatives through Integrated Computational Analysis.","date":"2026","source":"Current drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/42337902","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfDNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42482438","id":"PMC_42482438","title":"Discovery of Potent Antimalarial Agents Targeting Plasmodium falciparum DNA Gyrase B by Integrating Computational and Experimental Approaches.","date":"2026","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/42482438","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfGyrB"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7011,"output_tokens":1616,"usd":0.022637,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6694,"output_tokens":3218,"usd":0.05696,"stage2_stop_reason":"end_turn"},"total_usd":0.079597,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"PfGyrB (PF3D7_1239500) displays strong intrinsic ATPase activity and undergoes ATP-independent dimerization, unlike E. coli GyrB. The PfgyrB gene complemented an E. coli gyrase temperature-sensitive strain, and together with the N-terminal domain of PfGyrA it reconstituted DNA cleavage activity, confirming GyrB is a functional gyrase subunit.\",\n      \"method\": \"Recombinant protein expression, in vitro ATPase assay, E. coli complementation, DNA cleavage assay\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution, complementation, and multiple orthogonal functional assays in a single study\",\n      \"pmids\": [\"17220464\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PfGyrB (PF3D7_1239500) ATPase activity is inhibited by novobiocin, and novobiocin treatment of parasites in culture reduces the apicoplast/nuclear DNA ratio, indicating GyrB is involved in apicoplast DNA replication. Antibodies against recombinant PfGyrB confirmed the protein's presence in parasite lysates. Molecular modeling showed conservation of the ATPase domain fold with E. coli GyrB and the presence of a unique disordered loop adjacent to the ATPase domain.\",\n      \"method\": \"In vitro ATPase inhibition assay, parasite culture inhibition, apicoplast/nuclear DNA ratio measurement, immunoblotting with anti-recombinant PfGyrB antibodies, molecular modeling\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (biochemical inhibition, DNA quantification, immunodetection) in a single study linking GyrB activity to apicoplast DNA replication\",\n      \"pmids\": [\"17499371\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The ATP-binding domain of P. vivax GyrB (ortholog of PF3D7_1239500) expressed as a 43 kDa recombinant polypeptide shows intrinsic ATPase activity (Km = 0.27 mM, kcat = 0.051 s−1) that is sensitive to the bacterial gyrase inhibitor coumermycin.\",\n      \"method\": \"Recombinant protein expression, in vitro ATPase kinetics assay, coumermycin inhibition assay\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro enzymatic characterization but single lab, single species (P. vivax), no replication\",\n      \"pmids\": [\"15694492\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PfGyrB (PF3D7_1239500) was reconstituted with E. coli GyrA to form a functional hybrid gyrase enzyme. The compound purpurogallin (PPG) preferentially inhibits this hybrid enzyme over E. coli gyrase by disrupting DNA binding to the hybrid complex and consequently reducing DNA-induced ATPase activity of PfGyrB; binding studies showed PPG has higher affinity for PfGyrB than for E. coli GyrB.\",\n      \"method\": \"Hybrid enzyme reconstitution (PfGyrB + E. coli GyrA), supercoiling activity assay, ATPase assay, binding affinity measurement\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzyme reconstitution, mechanistic dissection (DNA binding disruption → ATPase reduction), binding studies, multiple orthogonal methods in single study\",\n      \"pmids\": [\"34339271\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"UNC8153 and Fexofenadine hydrochloride were identified as inhibitors of PfGyrB (PF3D7_1239500) ATPase activity in vitro and showed time-dependent antiplasmodial activity in parasite growth assays, including against an artemisinin-resistant C580Y strain; UNC8153 showed ~25-fold greater antiplasmodial activity than novobiocin at 96 h.\",\n      \"method\": \"Virtual screening, biochemical ATPase inhibition assay, parasite growth inhibition assay, morphological analysis\",\n      \"journal\": \"Chemical biology & drug design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro ATPase and parasite inhibition assays combined, but single lab, no mechanistic follow-up on GyrB-specific mode of action beyond ATPase inhibition\",\n      \"pmids\": [\"42482438\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfGyrB (PF3D7_1239500) is a nuclear-encoded, apicoplast-targeted DNA gyrase B subunit that possesses intrinsic ATPase activity (with unique ATP-independent dimerization not seen in bacterial GyrB), forms a functional heterotetramer with GyrA to introduce negative supercoils into DNA, is required for apicoplast DNA replication, and is inhibited by bacterial gyrase inhibitors (novobiocin, coumermycin) as well as by novel compounds (e.g. purpurogallin) that disrupt its DNA-binding and DNA-stimulated ATPase activities.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GyrB (PF3D7_1239500) is a functional DNA gyrase B subunit of Plasmodium falciparum that supplies the ATPase activity of an apicoplast-localized gyrase and is required for apicoplast DNA replication [#0, #1]. Recombinant PfGyrB displays strong intrinsic ATPase activity, complements an E. coli gyrase temperature-sensitive strain, and reconstitutes DNA cleavage activity together with the N-terminal domain of PfGyrA, confirming it acts as a genuine gyrase subunit; distinctively, it undergoes ATP-independent dimerization not seen in E. coli GyrB [#0]. Its ATPase activity is inhibited by the bacterial gyrase inhibitor novobiocin, and novobiocin treatment of cultured parasites lowers the apicoplast/nuclear DNA ratio, tying GyrB function to apicoplast genome maintenance [#1]. The enzyme is amenable to hybrid reconstitution with E. coli GyrA, in which purpurogallin preferentially inhibits the hybrid by disrupting DNA binding and thereby the DNA-stimulated ATPase activity of PfGyrB [#3]. GyrB's druggable ATPase activity makes it an antimalarial target, with additional inhibitors (UNC8153, fexofenadine) showing antiplasmodial activity including against an artemisinin-resistant strain [#4]. Beyond these enzymatic and pharmacological characterizations, no further mechanistic detail (e.g., in-parasite genetic knockout or structural determination) has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that the Plasmodium GyrB ATP-binding domain is an active, drug-sensitive ATPase addressed whether the parasite encodes a genuine gyrase B enzymatic module.\",\n      \"evidence\": \"Recombinant 43 kDa ATP-binding domain of P. vivax GyrB (ortholog of PF3D7_1239500) characterized by in vitro ATPase kinetics and coumermycin inhibition\",\n      \"pmids\": [\"15694492\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Shown for the P. vivax ortholog, not directly for PF3D7_1239500\",\n        \"Only the isolated ATP-binding domain, not full-length or holoenzyme\",\n        \"No demonstration of gyrase supercoiling or GyrA partnership\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium vivax\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Direct enzymatic reconstitution and complementation established PfGyrB as a bona fide gyrase subunit and revealed a parasite-specific ATP-independent dimerization property.\",\n      \"evidence\": \"Recombinant PfGyrB ATPase assay, E. coli gyrase ts-strain complementation, and DNA cleavage reconstitution with the N-terminal domain of PfGyrA\",\n      \"pmids\": [\"17220464\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Full supercoiling reconstitution with native PfGyrA not shown\",\n        \"Functional significance of ATP-independent dimerization unresolved\",\n        \"No in-parasite genetic evidence of essentiality\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linking GyrB inhibition to a fall in the apicoplast/nuclear DNA ratio connected the enzyme's biochemical activity to its cellular role in apicoplast DNA replication.\",\n      \"evidence\": \"In vitro novobiocin ATPase inhibition, apicoplast/nuclear DNA ratio measurement in novobiocin-treated cultures, anti-PfGyrB immunoblotting, and molecular modeling of the ATPase domain\",\n      \"pmids\": [\"17499371\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Apicoplast DNA effect is pharmacological, not from a GyrB-specific genetic perturbation\",\n        \"Subcellular localization inferred from function/modeling rather than imaging\",\n        \"Role of the unique disordered loop not tested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A hybrid PfGyrB/E. coli GyrA enzyme provided a tractable system to dissect a parasite-selective inhibitor's mechanism, showing inhibition proceeds through disrupted DNA binding and reduced DNA-stimulated ATPase activity.\",\n      \"evidence\": \"Hybrid enzyme reconstitution, supercoiling and ATPase assays, and binding-affinity measurements with purpurogallin\",\n      \"pmids\": [\"34339271\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Uses E. coli GyrA rather than native PfGyrA\",\n        \"Selectivity and efficacy against live parasites via this mechanism not established here\",\n        \"No structural model of the PfGyrB-inhibitor interaction\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Screening-derived ATPase inhibitors with antiplasmodial activity, including against an artemisinin-resistant strain, extended GyrB's status as an actionable antimalarial drug target.\",\n      \"evidence\": \"Virtual screening, biochemical ATPase inhibition, and parasite growth/morphology assays with UNC8153 and fexofenadine against wild-type and C580Y strains\",\n      \"pmids\": [\"42482438\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No mechanistic follow-up beyond ATPase inhibition\",\n        \"On-target engagement in parasites not confirmed\",\n        \"Selectivity over host targets not addressed\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PfGyrB is genetically essential in the parasite and how the holoenzyme is structurally organized and targeted to the apicoplast remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No conditional knockout/knockdown of PF3D7_1239500 in the corpus\",\n        \"No experimental structure of PfGyrB or the PfGyrA/PfGyrB holoenzyme\",\n        \"Apicoplast import signal and trafficking not directly characterized\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003918\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0005524\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0042803\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020011\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006265\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0006260\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"DNA gyrase heterotetramer (with PfGyrA)\",\n      \"Hybrid gyrase reconstituted with E. coli GyrA\"\n    ],\n    \"partners\": [\n      \"PfGyrA (N-terminal domain, reconstitution partner)\",\n      \"E. coli GyrA (hybrid enzyme partner)\"\n    ],\n    \"other_free_text\": [\n      \"Displays parasite-specific ATP-independent dimerization not seen in E. coli GyrB [#0]\",\n      \"Contains a unique disordered loop adjacent to the ATPase domain by molecular modeling [#1]\",\n      \"Inhibited by bacterial gyrase inhibitors novobiocin and coumermycin [#1, #2]\",\n      \"Inhibited by purpurogallin via disruption of DNA binding and DNA-stimulated ATPase activity [#3]\",\n      \"Inhibited by UNC8153 and fexofenadine, with antiplasmodial activity including against artemisinin-resistant C580Y parasites [#4]\",\n      \"Findings at idx #2 derive from the P. vivax ortholog, not PF3D7_1239500 directly\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1239500","name":null,"product":"DNA gyrase subunit B","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1454000","name":null,"product":"DNA gyrase subunit B, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1459600","name":null,"product":"DNA gyrase subunit B, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"GyrB","evaluation":null}