{"gene":"PF3D7_1244600","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2011,"finding":"The crystal structure of the catalytic domain of P. falciparum ARFGAP1 (PF3D7_1244600) was determined at 2.4 Å resolution by MAD phasing using the Zn2+ ion at the zinc-finger domain. The overall fold is similar to mammalian ARFGAPs, but several residues in the ARF1-interaction surface and the crystal dimer interface are unique to P. falciparum ARFGAP.","method":"X-ray crystallography (MAD phasing, 2.4 Å resolution)","journal":"Acta crystallographica. Section F, Structural biology and crystallization communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure solved with experimental phasing at 2.4 Å; single study but rigorous structural method with functional-surface annotation","pmids":["22102228"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"The GAP domains of both P. falciparum ArfGAPs (including the one encoded by PF3D7_1244600) stimulate GTP hydrolysis on truncated PfArf1 to a level equivalent to human ArfGAP1, as measured by an in vitro colorimetric GTPase assay. However, unlike human ArfGAP1, the P. falciparum GAP domains are insensitive to the inhibitor QS11. A novel compound was identified that selectively inhibits one of the P. falciparum GAP domains (IC50 4.7 µM).","method":"In vitro colorimetric microtiter plate-based GTPase assay with recombinant GAP domain proteins","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro enzymatic assay demonstrating GAP activity, but single lab and the two P. falciparum ArfGAPs are not individually distinguished in the abstract","pmids":["32144363"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1244600 (ARFGAP1) encodes a zinc-finger-containing GAP-domain protein whose catalytic domain crystal structure at 2.4 Å is similar to mammalian ARFGAPs but has unique residues at the ARF1-interaction surface; its recombinant GAP domain stimulates GTP hydrolysis on PfArf1 in vitro at a level equivalent to human ArfGAP1 yet is insensitive to the human ArfGAP1 inhibitor QS11, consistent with a role in deactivating PfArf1 during vesicular trafficking in the parasite."},"narrative":{"mechanistic_narrative":"PF3D7_1244600 (ARFGAP1) encodes a zinc-finger-containing ADP-ribosylation factor GTPase-activating protein of Plasmodium falciparum whose catalytic domain adopts a fold similar to mammalian ARFGAPs but carries residues unique to P. falciparum at both the ARF1-interaction surface and the crystal dimer interface [PMID:22102228]. Its recombinant GAP domain stimulates GTP hydrolysis on truncated PfArf1 in vitro to a level equivalent to human ArfGAP1, establishing it as a catalytically active ARF GTPase-activating protein [PMID:32144363]. Unlike human ArfGAP1, the P. falciparum GAP domain is insensitive to the inhibitor QS11, and a distinct compound selectively inhibiting a P. falciparum GAP domain was identified [PMID:32144363]. Beyond this structural and in vitro enzymatic characterization, the cellular localization, in vivo function, and physiological role of PF3D7_1244600 have not been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Whether P. falciparum ARFGAP1 shares the architecture of mammalian ARFGAPs and whether it presents parasite-specific features was unknown; solving its catalytic domain structure defined both its conserved fold and the residues distinguishing it from the host enzyme.","evidence":"X-ray crystallography of the catalytic domain by MAD phasing at 2.4 Å resolution using the zinc-finger Zn2+ ion","pmids":["22102228"],"confidence":"High","gaps":["Structure captures only the isolated catalytic domain, not the full-length protein or an ARF1-bound complex","Functional consequence of the parasite-unique ARF1-interaction surface residues was not tested in this study","No cellular localization or in vivo role established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Whether the ARFGAP1 catalytic domain is enzymatically functional and pharmacologically distinct from the human enzyme was untested; an in vitro GTPase assay demonstrated GAP activity on PfArf1 and revealed insensitivity to the human inhibitor QS11 plus a selective inhibitor of a parasite GAP domain.","evidence":"In vitro colorimetric microtiter plate GTPase assay with recombinant GAP domain proteins and inhibitor testing","pmids":["32144363"],"confidence":"Medium","gaps":["The two P. falciparum ArfGAPs were not individually distinguished, so activity cannot be attributed solely to PF3D7_1244600 from the abstract","Assay used truncated PfArf1 rather than the full-length substrate in a membrane context","The selective inhibitor's target GAP domain identity and cellular efficacy remain undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The in vivo function, subcellular localization, vesicular-trafficking role, and essentiality of PF3D7_1244600 in the parasite remain unestablished.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cellular or genetic characterization (knockout, knockdown, localization) in the corpus","No demonstration of a trafficking phenotype linked to ARFGAP1 activity","No confirmation that observed GAP activity operates on native membrane-bound PfArf1 in vivo"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFARF1 (ADP-RIBOSYLATION FACTOR 1; SUBSTRATE OF ARFGAP1 GTPASE-ACTIVATING ACTIVITY) [#1]"],"other_free_text":["Catalytic domain crystallized at 2.4 Å with a zinc-finger domain coordinating Zn2+; fold similar to mammalian ARFGAPs with parasite-unique residues at the ARF1-interaction surface and dimer interface [#0]","Recombinant GAP domain stimulates GTP hydrolysis on truncated PfArf1 at a level equivalent to human ArfGAP1 [#1]","Insensitive to the human ArfGAP1 inhibitor QS11; a distinct compound selectively inhibits a P. falciparum GAP domain (IC50 4.7 µM) [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"11555294","id":"PMC_11555294","title":"A point mutation in an unusual Sec7 domain is linked to brefeldin A resistance in a Plasmodium falciparum line generated by drug selection.","date":"2001","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11555294","citation_count":21,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"6307262","id":"PMC_6307262","title":"ADP-ribosyltransferase in Plasmodium (malaria parasites).","date":"1983","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/6307262","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9247933","id":"PMC_9247933","title":"Identification and characterization of an ADP-ribosylation factor in Plasmodium falciparum.","date":"1997","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9247933","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9084044","id":"PMC_9084044","title":"Cloning and characterization of Plasmodium falciparum ADP-ribosylation factor and factor-like genes.","date":"1997","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9084044","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21045287","id":"PMC_21045287","title":"Structure of Plasmodium falciparum ADP-ribosylation factor 1.","date":"2010","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/21045287","citation_count":8,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15500915","id":"PMC_15500915","title":"Double cross-over gene replacement within the sec 7 domain of a GDP-GTP exchange factor from Plasmodium falciparum allows the generation of a transgenic brefeldin A-resistant parasite line.","date":"2004","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15500915","citation_count":8,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38349168","id":"PMC_38349168","title":"Toxoplasma and Plasmodium associate with host Arfs during infection.","date":"2024","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/38349168","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":true,"competing_organism_match":"Toxoplasma","competing_organism_only":true},{"pmid":"32144363","id":"PMC_32144363","title":"Detection of the in vitro modulation of Plasmodium falciparum Arf1 by Sec7 and ArfGAP domains using a colorimetric plate-based assay.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32144363","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARFGAP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22102228","id":"PMC_22102228","title":"Structure of the catalytic domain of Plasmodium falciparum ARF GTPase-activating protein (ARFGAP).","date":"2011","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22102228","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ADP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6235,"output_tokens":783,"usd":0.015225,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5457,"output_tokens":1821,"usd":0.036405,"stage2_stop_reason":"end_turn"},"total_usd":0.05163,"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\": 2011,\n      \"finding\": \"The crystal structure of the catalytic domain of P. falciparum ARFGAP1 (PF3D7_1244600) was determined at 2.4 Å resolution by MAD phasing using the Zn2+ ion at the zinc-finger domain. The overall fold is similar to mammalian ARFGAPs, but several residues in the ARF1-interaction surface and the crystal dimer interface are unique to P. falciparum ARFGAP.\",\n      \"method\": \"X-ray crystallography (MAD phasing, 2.4 Å resolution)\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology and crystallization communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure solved with experimental phasing at 2.4 Å; single study but rigorous structural method with functional-surface annotation\",\n      \"pmids\": [\"22102228\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The GAP domains of both P. falciparum ArfGAPs (including the one encoded by PF3D7_1244600) stimulate GTP hydrolysis on truncated PfArf1 to a level equivalent to human ArfGAP1, as measured by an in vitro colorimetric GTPase assay. However, unlike human ArfGAP1, the P. falciparum GAP domains are insensitive to the inhibitor QS11. A novel compound was identified that selectively inhibits one of the P. falciparum GAP domains (IC50 4.7 µM).\",\n      \"method\": \"In vitro colorimetric microtiter plate-based GTPase assay with recombinant GAP domain proteins\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro enzymatic assay demonstrating GAP activity, but single lab and the two P. falciparum ArfGAPs are not individually distinguished in the abstract\",\n      \"pmids\": [\"32144363\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1244600 (ARFGAP1) encodes a zinc-finger-containing GAP-domain protein whose catalytic domain crystal structure at 2.4 Å is similar to mammalian ARFGAPs but has unique residues at the ARF1-interaction surface; its recombinant GAP domain stimulates GTP hydrolysis on PfArf1 in vitro at a level equivalent to human ArfGAP1 yet is insensitive to the human ArfGAP1 inhibitor QS11, consistent with a role in deactivating PfArf1 during vesicular trafficking in the parasite.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PF3D7_1244600 (ARFGAP1) encodes a zinc-finger-containing ADP-ribosylation factor GTPase-activating protein of Plasmodium falciparum whose catalytic domain adopts a fold similar to mammalian ARFGAPs but carries residues unique to P. falciparum at both the ARF1-interaction surface and the crystal dimer interface [#0]. Its recombinant GAP domain stimulates GTP hydrolysis on truncated PfArf1 in vitro to a level equivalent to human ArfGAP1, establishing it as a catalytically active ARF GTPase-activating protein [#1]. Unlike human ArfGAP1, the P. falciparum GAP domain is insensitive to the inhibitor QS11, and a distinct compound selectively inhibiting a P. falciparum GAP domain was identified [#1]. Beyond this structural and in vitro enzymatic characterization, the cellular localization, in vivo function, and physiological role of PF3D7_1244600 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether P. falciparum ARFGAP1 shares the architecture of mammalian ARFGAPs and whether it presents parasite-specific features was unknown; solving its catalytic domain structure defined both its conserved fold and the residues distinguishing it from the host enzyme.\",\n      \"evidence\": \"X-ray crystallography of the catalytic domain by MAD phasing at 2.4 Å resolution using the zinc-finger Zn2+ ion\",\n      \"pmids\": [\"22102228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure captures only the isolated catalytic domain, not the full-length protein or an ARF1-bound complex\",\n        \"Functional consequence of the parasite-unique ARF1-interaction surface residues was not tested in this study\",\n        \"No cellular localization or in vivo role established\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether the ARFGAP1 catalytic domain is enzymatically functional and pharmacologically distinct from the human enzyme was untested; an in vitro GTPase assay demonstrated GAP activity on PfArf1 and revealed insensitivity to the human inhibitor QS11 plus a selective inhibitor of a parasite GAP domain.\",\n      \"evidence\": \"In vitro colorimetric microtiter plate GTPase assay with recombinant GAP domain proteins and inhibitor testing\",\n      \"pmids\": [\"32144363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The two P. falciparum ArfGAPs were not individually distinguished, so activity cannot be attributed solely to PF3D7_1244600 from the abstract\",\n        \"Assay used truncated PfArf1 rather than the full-length substrate in a membrane context\",\n        \"The selective inhibitor's target GAP domain identity and cellular efficacy remain undefined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo function, subcellular localization, vesicular-trafficking role, and essentiality of PF3D7_1244600 in the parasite remain unestablished.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cellular or genetic characterization (knockout, knockdown, localization) in the corpus\",\n        \"No demonstration of a trafficking phenotype linked to ARFGAP1 activity\",\n        \"No confirmation that observed GAP activity operates on native membrane-bound PfArf1 in vivo\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008270\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016192\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PfArf1 (ADP-ribosylation factor 1; substrate of ARFGAP1 GTPase-activating activity) [#1]\"],\n    \"other_free_text\": [\n      \"Catalytic domain crystallized at 2.4 Å with a zinc-finger domain coordinating Zn2+; fold similar to mammalian ARFGAPs with parasite-unique residues at the ARF1-interaction surface and dimer interface [#0]\",\n      \"Recombinant GAP domain stimulates GTP hydrolysis on truncated PfArf1 at a level equivalent to human ArfGAP1 [#1]\",\n      \"Insensitive to the human ArfGAP1 inhibitor QS11; a distinct compound selectively inhibits a P. falciparum GAP domain (IC50 4.7 µM) [#1]\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1244600","name":null,"product":"ADP-ribosylation factor GTPase-activating protein 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1457800","name":null,"product":"ADP-ribosylation factor GTPase-activating protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1464300","name":null,"product":"ADP-ribosylation factor GTPase-activating protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ARFGAP1","evaluation":null}