{"gene":"PF3D7_1105400","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2014,"finding":"The cryo-EM structure of the P. falciparum 80S ribosome at 3.2 Å resolution was determined, revealing the architecture of the small (40S) subunit, of which S4 (PF3D7_1105400) is a constituent ribosomal protein. The structure showed emetine binding at the E-site of the small subunit, blocking mRNA/tRNA translocation.","method":"Cryo-EM structure determination at 3.2 Å resolution","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution cryo-EM structure of the intact ribosome establishes S4 as a structural component of the 40S small subunit, but no functional experiment was performed specifically on S4 itself; its role is inferred from complex membership","pmids":["24913268"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Five cryo-EM reconstructions of P. falciparum 80S ribosomes purified from blood-stage schizonts at sub-nanometer resolution were obtained and atomic models built by flexible fitting, further characterizing the structural context of the 40S small subunit (of which S4/PF3D7_1105400 is a component) in multiple functional states during translation.","method":"Cryo-EM with flexible fitting and atomic model building","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — multi-state cryo-EM structures of the intact ribosome place S4 structurally within the 40S subunit across translational states, but no experiment directly interrogates S4 function or interactions","pmids":["26432834"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"A 3.2 Å cryo-EM structure of the P. falciparum 80S ribosome with (+)-mefloquine bound to the GTPase-associated centre was resolved; S4 (PF3D7_1105400) is a structural constituent of the 40S small subunit visualized in this complex. Mutagenesis of mefloquine-binding residues (in the large subunit GTPase-associated centre) confirmed the parasite-killing mechanism, establishing the ribosome as mefloquine's target.","method":"Cryo-EM structure determination at 3.2 Å; site-directed mutagenesis of binding-site residues with resistance phenotype readout","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution structure and mutagenesis confirm ribosome as drug target and structurally place S4 within the 40S subunit, but no experiment directly tests S4's individual contribution","pmids":["28288098"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Eight high-resolution cryo-ET structures of the native P. falciparum 80S ribosome in actively translating states inside infected erythrocytes were determined using in situ cryo-electron tomography, providing structural detail of the 40S small subunit (containing S4/PF3D7_1105400) within the native cellular context and revealing new molecular details of the malarial translation elongation cycle.","method":"In situ cryo-electron tomography (cryo-ET) at high resolution inside infected erythrocytes","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in-cell high-resolution structural data confirms S4's membership in the physiologically assembled 40S subunit during active translation, but no experiment isolates S4's specific function","pmids":["40825879"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1105400 (S4) is established as a structural component of the P. falciparum 40S ribosomal small subunit, as evidenced by multiple cryo-EM and in situ cryo-ET structures of the intact 80S ribosome; no experiment has yet directly interrogated S4's individual function, specific interactions, or contribution to translation beyond its membership in this complex."},"narrative":{"mechanistic_narrative":"PF3D7_1105400 (S4) is a constituent ribosomal protein of the small (40S) subunit of the Plasmodium falciparum 80S ribosome, established through high-resolution structural characterization of the intact translation machinery [PMID:24913268, PMID:40825879]. It is resolved as a structural component of the 40S subunit across multiple cryo-EM reconstructions of ribosomes captured in distinct functional states during translation [PMID:26432834], and it is present in the natively assembled, actively translating ribosome imaged in situ within infected erythrocytes [PMID:40825879]. The same structural studies define the P. falciparum ribosome as the target of antimalarials including emetine, which blocks translocation at the small-subunit E-site [PMID:24913268], and mefloquine, which binds the large-subunit GTPase-associated centre [PMID:28288098]. Beyond its membership in the 40S subunit as visualized in these structures, no experiment in the available corpus has directly interrogated the individual function, specific interactions, or translational contribution of S4 itself.","teleology":[{"year":2014,"claim":"Before this work the molecular architecture of the P. falciparum ribosome was unknown; determining the 80S structure placed S4 as a defined structural component of the 40S small subunit and revealed how emetine blocks translocation at the small-subunit E-site.","evidence":"Cryo-EM structure determination of the intact 80S ribosome at 3.2 Å resolution","pmids":["24913268"],"confidence":"Medium","gaps":["No functional experiment isolates S4's individual contribution to translation","S4-specific interactions within the 40S subunit not dissected","Role inferred solely from complex membership"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"To understand the ribosome across the translation cycle, multi-state reconstructions were obtained, positioning S4 structurally within the 40S subunit in several functional conformations rather than a single static state.","evidence":"Five sub-nanometer cryo-EM reconstructions from blood-stage schizonts with flexible fitting and atomic model building","pmids":["26432834"],"confidence":"Medium","gaps":["No experiment interrogates whether S4 changes role across the functional states","S4 conformational dynamics not analyzed individually"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"To validate the ribosome as an antimalarial target, the mefloquine-bound structure and binding-site mutagenesis confirmed drug action at the GTPase-associated centre, with S4 again resolved as part of the 40S subunit in the complex.","evidence":"Cryo-EM at 3.2 Å plus site-directed mutagenesis of binding-site residues with resistance phenotype readout","pmids":["28288098"],"confidence":"Medium","gaps":["Drug-binding and mutagenesis concern the large-subunit GTPase-associated centre, not S4","No functional role attributed to S4"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"To move from purified particles to physiological context, in situ cryo-ET captured the native ribosome during active translation inside infected cells, confirming S4's membership in the physiologically assembled, translating 40S subunit.","evidence":"In situ cryo-electron tomography at high resolution inside infected erythrocytes, eight structures across elongation states","pmids":["40825879"],"confidence":"Medium","gaps":["Still no isolation of S4-specific function or interactions","No perturbation of S4 to test its necessity for elongation"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"What is the individual functional contribution of S4 to 40S assembly, mRNA/tRNA handling, or translation fidelity, and what are its specific molecular partners beyond bulk 40S membership?","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genetic or biochemical perturbation of S4 reported","No S4-specific interaction map","No essentiality or knockdown data for S4 in the corpus"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["40S small ribosomal subunit (P. falciparum 80S ribosome)"],"partners":[],"other_free_text":["S4 is resolved only as a structural constituent of the 40S subunit; the P. falciparum ribosome is the validated target of emetine (E-site, translocation block) [#0] and mefloquine (large-subunit GTPase-associated centre) [#2], but these drug interactions are not attributed to S4 itself.","No experiment in the corpus directly interrogates S4's individual function, specific interactions, or contribution to translation beyond 40S membership."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"24913268","id":"PMC_24913268","title":"Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/24913268","citation_count":276,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26432834","id":"PMC_26432834","title":"Dynamical features of the Plasmodium falciparum ribosome during translation.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26432834","citation_count":46,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40825879","id":"PMC_40825879","title":"Integrated structural biology of the native malarial translation machinery and its inhibition by an antimalarial drug.","date":"2025","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40825879","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40480224","id":"PMC_40480224","title":"Antimalarial drug artemisinin stabilizes PfRACK1 binding to the ribosome.","date":"2025","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/40480224","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28288098","id":"PMC_28288098","title":"Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis.","date":"2017","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28288098","citation_count":138,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32469313","id":"PMC_32469313","title":"Plasmodium falciparum translational machinery condones polyadenosine repeats.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32469313","citation_count":21,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37053161","id":"PMC_37053161","title":"Ribosome heterogeneity and specialization of Plasmodium parasites.","date":"2023","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/37053161","citation_count":14,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31866984","id":"PMC_31866984","title":"Adaptation of Translational Machinery in Malaria Parasites to Accommodate Translation of Poly-Adenosine Stretches Throughout Its Life Cycle.","date":"2019","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31866984","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34017052","id":"PMC_34017052","title":"Structural analysis of the SRP Alu domain from Plasmodium falciparum reveals a non-canonical open conformation.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/34017052","citation_count":8,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35452681","id":"PMC_35452681","title":"Association of the receptor for activated C-kinase 1 with ribosomes in Plasmodium falciparum.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35452681","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41315737","id":"PMC_41315737","title":"MAP-X reveals distinct protein complex dynamics across Plasmodium falciparum blood stages.","date":"2025","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41315737","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42001110","id":"PMC_42001110","title":"Targeting protein-protein interactions in Plasmodium: from asexual replication to sexual development.","date":"2026","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/42001110","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"citation_expansion","match_terms":["fwd_cite"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7687,"output_tokens":1247,"usd":0.020883,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6085,"output_tokens":1997,"usd":0.040175,"stage2_stop_reason":"end_turn"},"total_usd":0.061058,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"The cryo-EM structure of the P. falciparum 80S ribosome at 3.2 Å resolution was determined, revealing the architecture of the small (40S) subunit, of which S4 (PF3D7_1105400) is a constituent ribosomal protein. The structure showed emetine binding at the E-site of the small subunit, blocking mRNA/tRNA translocation.\",\n      \"method\": \"Cryo-EM structure determination at 3.2 Å resolution\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution cryo-EM structure of the intact ribosome establishes S4 as a structural component of the 40S small subunit, but no functional experiment was performed specifically on S4 itself; its role is inferred from complex membership\",\n      \"pmids\": [\"24913268\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Five cryo-EM reconstructions of P. falciparum 80S ribosomes purified from blood-stage schizonts at sub-nanometer resolution were obtained and atomic models built by flexible fitting, further characterizing the structural context of the 40S small subunit (of which S4/PF3D7_1105400 is a component) in multiple functional states during translation.\",\n      \"method\": \"Cryo-EM with flexible fitting and atomic model building\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — multi-state cryo-EM structures of the intact ribosome place S4 structurally within the 40S subunit across translational states, but no experiment directly interrogates S4 function or interactions\",\n      \"pmids\": [\"26432834\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A 3.2 Å cryo-EM structure of the P. falciparum 80S ribosome with (+)-mefloquine bound to the GTPase-associated centre was resolved; S4 (PF3D7_1105400) is a structural constituent of the 40S small subunit visualized in this complex. Mutagenesis of mefloquine-binding residues (in the large subunit GTPase-associated centre) confirmed the parasite-killing mechanism, establishing the ribosome as mefloquine's target.\",\n      \"method\": \"Cryo-EM structure determination at 3.2 Å; site-directed mutagenesis of binding-site residues with resistance phenotype readout\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution structure and mutagenesis confirm ribosome as drug target and structurally place S4 within the 40S subunit, but no experiment directly tests S4's individual contribution\",\n      \"pmids\": [\"28288098\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Eight high-resolution cryo-ET structures of the native P. falciparum 80S ribosome in actively translating states inside infected erythrocytes were determined using in situ cryo-electron tomography, providing structural detail of the 40S small subunit (containing S4/PF3D7_1105400) within the native cellular context and revealing new molecular details of the malarial translation elongation cycle.\",\n      \"method\": \"In situ cryo-electron tomography (cryo-ET) at high resolution inside infected erythrocytes\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in-cell high-resolution structural data confirms S4's membership in the physiologically assembled 40S subunit during active translation, but no experiment isolates S4's specific function\",\n      \"pmids\": [\"40825879\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1105400 (S4) is established as a structural component of the P. falciparum 40S ribosomal small subunit, as evidenced by multiple cryo-EM and in situ cryo-ET structures of the intact 80S ribosome; no experiment has yet directly interrogated S4's individual function, specific interactions, or contribution to translation beyond its membership in this complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1105400 (S4) is a constituent ribosomal protein of the small (40S) subunit of the Plasmodium falciparum 80S ribosome, established through high-resolution structural characterization of the intact translation machinery [#0, #3]. It is resolved as a structural component of the 40S subunit across multiple cryo-EM reconstructions of ribosomes captured in distinct functional states during translation [#1], and it is present in the natively assembled, actively translating ribosome imaged in situ within infected erythrocytes [#3]. The same structural studies define the P. falciparum ribosome as the target of antimalarials including emetine, which blocks translocation at the small-subunit E-site [#0], and mefloquine, which binds the large-subunit GTPase-associated centre [#2]. Beyond its membership in the 40S subunit as visualized in these structures, no experiment in the available corpus has directly interrogated the individual function, specific interactions, or translational contribution of S4 itself.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Before this work the molecular architecture of the P. falciparum ribosome was unknown; determining the 80S structure placed S4 as a defined structural component of the 40S small subunit and revealed how emetine blocks translocation at the small-subunit E-site.\",\n      \"evidence\": \"Cryo-EM structure determination of the intact 80S ribosome at 3.2 Å resolution\",\n      \"pmids\": [\"24913268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional experiment isolates S4's individual contribution to translation\", \"S4-specific interactions within the 40S subunit not dissected\", \"Role inferred solely from complex membership\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"To understand the ribosome across the translation cycle, multi-state reconstructions were obtained, positioning S4 structurally within the 40S subunit in several functional conformations rather than a single static state.\",\n      \"evidence\": \"Five sub-nanometer cryo-EM reconstructions from blood-stage schizonts with flexible fitting and atomic model building\",\n      \"pmids\": [\"26432834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experiment interrogates whether S4 changes role across the functional states\", \"S4 conformational dynamics not analyzed individually\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"To validate the ribosome as an antimalarial target, the mefloquine-bound structure and binding-site mutagenesis confirmed drug action at the GTPase-associated centre, with S4 again resolved as part of the 40S subunit in the complex.\",\n      \"evidence\": \"Cryo-EM at 3.2 Å plus site-directed mutagenesis of binding-site residues with resistance phenotype readout\",\n      \"pmids\": [\"28288098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Drug-binding and mutagenesis concern the large-subunit GTPase-associated centre, not S4\", \"No functional role attributed to S4\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"To move from purified particles to physiological context, in situ cryo-ET captured the native ribosome during active translation inside infected cells, confirming S4's membership in the physiologically assembled, translating 40S subunit.\",\n      \"evidence\": \"In situ cryo-electron tomography at high resolution inside infected erythrocytes, eight structures across elongation states\",\n      \"pmids\": [\"40825879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Still no isolation of S4-specific function or interactions\", \"No perturbation of S4 to test its necessity for elongation\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What is the individual functional contribution of S4 to 40S assembly, mRNA/tRNA handling, or translation fidelity, and what are its specific molecular partners beyond bulk 40S membership?\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic or biochemical perturbation of S4 reported\", \"No S4-specific interaction map\", \"No essentiality or knockdown data for S4 in the corpus\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003735\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0022627\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006412\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\n      \"40S small ribosomal subunit (P. falciparum 80S ribosome)\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"S4 is resolved only as a structural constituent of the 40S subunit; the P. falciparum ribosome is the validated target of emetine (E-site, translocation block) [#0] and mefloquine (large-subunit GTPase-associated centre) [#2], but these drug interactions are not attributed to S4 itself.\",\n      \"No experiment in the corpus directly interrogates S4's individual function, specific interactions, or contribution to translation beyond 40S membership.\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1105400","name":null,"product":"40S ribosomal protein S4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0941500","name":null,"product":"40S ribosomal protein S4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0903000","name":null,"product":"40S ribosomal protein S4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"RPS4","evaluation":null}