{"gene":"PF3D7_1215900","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2020,"finding":"SR10 (PF3D7_1215900) has a 24 h transcriptional rhythm, and genetic disruption of SR10 in rodent malaria parasites (P. chabaudi) shortens the intra-erythrocytic developmental cycle (IDC) by 2–3 h, establishing SR10 as a regulator of IDC duration and coordination with host daily rhythms. Loss of SR10 also disrupts multiple processes including DNA replication and the ubiquitin/proteasome pathways.","method":"In vivo genetic disruption (loss-of-function) in rodent malaria parasites combined with transcriptomic profiling; in vitro and in vivo time-series analyses of transcriptional rhythmicity","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic disruption with defined cellular phenotype (IDC shortening), supported by transcriptomic and pathway analyses; single study, single lab","pmids":["32488076"],"is_preprint":false,"attribution":[{"species":"Plasmodium chabaudi","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"SR10 (PF3D7_1215900) is expressed in asexual and sexual blood stages of P. falciparum and localizes to the endoplasmic reticulum, demonstrated by co-localization with the ER-resident protein ERC and confirmed by co-immunoprecipitation showing physical association with ERC. Gene disruption of SR10 impairs intraerythrocytic replication and strongly reduces gametocyte numbers.","method":"Co-localization assays, co-immunoprecipitation (Co-IP), and gene disruption (loss-of-function) with phenotypic readouts (replication rate, gametocyte counts)","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and co-localization for ER association, plus KO phenotype in two life-cycle stages; single lab, two orthogonal methods","pmids":["32890576"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"SR10 (PF3D7_1215900) functions as a G-protein-coupled-like receptor: antimalarial drugs chloroquine, dihydroartemisinin, piperaquine-tetraphosphate, and primaquine diphosphate act as agonists inducing coupling of SR10 with human Gi/Gq proteins, established by biochemical reconstitution and cryo-EM structural analysis. Bradykinin was identified as an endogenous agonist activating SR10, identified via proteomic profiling. Ligand binding sites and receptor conformational changes were characterized by mutagenesis and FlAsH-BRET assays.","method":"Biochemical reconstitution, cryo-EM structural analysis, mutagenesis, FlAsH-BRET assays, proteomic profiling","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with reconstitution, mutagenesis, and FlAsH-BRET in a single study providing multiple orthogonal lines of evidence; single lab but highly rigorous methods","pmids":["41280702"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"SR10 (PF3D7_1215900) is a serpentine/G-protein-coupled-like receptor localized to the endoplasmic reticulum of P. falciparum blood stages that regulates intra-erythrocytic developmental cycle duration and coordination with host circadian rhythms; it couples to human Gi/Gq proteins upon binding antimalarial drugs (chloroquine, dihydroartemisinin, piperaquine, primaquine) and the host peptide bradykinin, and its loss impairs asexual replication, disrupts DNA replication and ubiquitin/proteasome pathways, and strongly reduces gametocyte production."},"narrative":{"mechanistic_narrative":"SR10 (PF3D7_1215900) is a serpentine/G-protein-coupled-like receptor of Plasmodium that functions to time and coordinate the intra-erythrocytic developmental cycle (IDC) with host daily rhythms and to sustain both asexual replication and gametocyte production [PMID:32488076, PMID:32890576]. SR10 transcription oscillates with a 24 h period, and its genetic disruption in the rodent parasite P. chabaudi shortens the IDC by 2–3 h while perturbing DNA replication and ubiquitin/proteasome pathways, establishing it as a regulator of developmental cycle duration [PMID:32488076]. In P. falciparum, SR10 is expressed in asexual and sexual blood stages and localizes to the endoplasmic reticulum, where it physically associates with the ER-resident protein ERC; its loss impairs intraerythrocytic replication and strongly reduces gametocyte numbers [PMID:32890576]. As a receptor, SR10 couples to human Gi/Gq proteins upon activation by antimalarial drugs (chloroquine, dihydroartemisinin, piperaquine-tetraphosphate, primaquine diphosphate) acting as agonists and by the host peptide bradykinin as an endogenous agonist, with ligand-binding sites and activating conformational changes resolved by cryo-EM, mutagenesis, and FlAsH-BRET [PMID:41280702].","teleology":[{"year":2020,"claim":"Whether any parasite factor sets the pace of the intra-erythrocytic cycle and aligns it to host rhythms was unresolved; disruption of SR10 defined it as a timekeeping regulator.","evidence":"In vivo loss-of-function disruption in P. chabaudi with transcriptomic and time-series rhythmicity profiling","pmids":["32488076"],"confidence":"Medium","gaps":["Molecular mechanism linking SR10 to IDC length is not defined","How SR10 impinges on DNA replication and ubiquitin/proteasome pathways is unknown","Rodent-parasite phenotype not directly demonstrated for the IDC-timing role in P. falciparum"],"attribution":[{"species":"Plasmodium chabaudi","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The subcellular site of SR10 action and its stage-specific requirement were unknown; localization and disruption studies placed it at the ER and tied it to both replication and sexual commitment.","evidence":"Co-localization and reciprocal Co-IP with ER-resident ERC, plus gene disruption scored for replication and gametocyte counts in P. falciparum","pmids":["32890576"],"confidence":"Medium","gaps":["Functional consequence of the SR10–ERC association is uncharacterized","How an ER-localized receptor controls gametocytogenesis is unresolved","Single-lab evidence for the ER localization"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Whether SR10 is a bona fide signaling receptor and what activates it were open; structural and biochemical reconstitution established it as a GPCR-like receptor coupling to Gi/Gq and identified drug and peptide agonists.","evidence":"Biochemical reconstitution, cryo-EM, mutagenesis, FlAsH-BRET, and proteomic profiling of ligands in P. falciparum","pmids":["41280702"],"confidence":"High","gaps":["Endogenous downstream signaling pathway in the parasite is not mapped","Physiological relevance of bradykinin activation in vivo is not established","Whether drug agonism relates to antimalarial mechanism of action is unaddressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How ligand binding and Gi/Gq coupling mechanistically connect to IDC timing, ER function, DNA replication, and gametocyte production remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No signaling-to-phenotype causal chain linking receptor activation to developmental control","Native endogenous agonist and its source in the host–parasite context unconfirmed","No integration of the ER localization with GPCR-like signaling model"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["ERC (ER-RESIDENT PROTEIN, CO-IP AND CO-LOCALIZATION) [#1]","HUMAN GI/GQ PROTEINS (HETEROLOGOUS COUPLING PARTNERS) [#2]"],"other_free_text":["24 h transcriptional rhythm; disruption shortens the intra-erythrocytic developmental cycle by 2–3 h in P. chabaudi [#0]","Loss disrupts DNA replication and ubiquitin/proteasome pathways [#0]","Disruption impairs intraerythrocytic replication and strongly reduces gametocyte numbers in P. falciparum [#1]","Antimalarial drug agonists: chloroquine, dihydroartemisinin, piperaquine-tetraphosphate, primaquine diphosphate [#2]","Endogenous agonist bradykinin identified by proteomic profiling [#2]","Ligand-binding sites and conformational changes defined by cryo-EM, mutagenesis, and FlAsH-BRET [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"32488076","id":"PMC_32488076","title":"Malaria parasites regulate intra-erythrocytic development duration via serpentine receptor 10 to coordinate with host rhythms.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32488076","citation_count":46,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SR10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32890576","id":"PMC_32890576","title":"The endoplasmic reticulum-resident serpentine receptor SR10 has important functions for asexual and sexual blood stage development of Plasmodium falciparum.","date":"2020","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/32890576","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SR10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41280702","id":"PMC_41280702","title":"Identification of antimalarial drugs and bradykinin as ligands of the Plasmodium membrane protein PfSR10.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41280702","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SR10","PfSR10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4088,"output_tokens":1164,"usd":0.014862,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5986,"output_tokens":2290,"usd":0.04359,"stage2_stop_reason":"end_turn"},"total_usd":0.058452,"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\": 2020,\n      \"finding\": \"SR10 (PF3D7_1215900) has a 24 h transcriptional rhythm, and genetic disruption of SR10 in rodent malaria parasites (P. chabaudi) shortens the intra-erythrocytic developmental cycle (IDC) by 2–3 h, establishing SR10 as a regulator of IDC duration and coordination with host daily rhythms. Loss of SR10 also disrupts multiple processes including DNA replication and the ubiquitin/proteasome pathways.\",\n      \"method\": \"In vivo genetic disruption (loss-of-function) in rodent malaria parasites combined with transcriptomic profiling; in vitro and in vivo time-series analyses of transcriptional rhythmicity\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic disruption with defined cellular phenotype (IDC shortening), supported by transcriptomic and pathway analyses; single study, single lab\",\n      \"pmids\": [\"32488076\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium chabaudi\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SR10 (PF3D7_1215900) is expressed in asexual and sexual blood stages of P. falciparum and localizes to the endoplasmic reticulum, demonstrated by co-localization with the ER-resident protein ERC and confirmed by co-immunoprecipitation showing physical association with ERC. Gene disruption of SR10 impairs intraerythrocytic replication and strongly reduces gametocyte numbers.\",\n      \"method\": \"Co-localization assays, co-immunoprecipitation (Co-IP), and gene disruption (loss-of-function) with phenotypic readouts (replication rate, gametocyte counts)\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and co-localization for ER association, plus KO phenotype in two life-cycle stages; single lab, two orthogonal methods\",\n      \"pmids\": [\"32890576\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SR10 (PF3D7_1215900) functions as a G-protein-coupled-like receptor: antimalarial drugs chloroquine, dihydroartemisinin, piperaquine-tetraphosphate, and primaquine diphosphate act as agonists inducing coupling of SR10 with human Gi/Gq proteins, established by biochemical reconstitution and cryo-EM structural analysis. Bradykinin was identified as an endogenous agonist activating SR10, identified via proteomic profiling. Ligand binding sites and receptor conformational changes were characterized by mutagenesis and FlAsH-BRET assays.\",\n      \"method\": \"Biochemical reconstitution, cryo-EM structural analysis, mutagenesis, FlAsH-BRET assays, proteomic profiling\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with reconstitution, mutagenesis, and FlAsH-BRET in a single study providing multiple orthogonal lines of evidence; single lab but highly rigorous methods\",\n      \"pmids\": [\"41280702\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"SR10 (PF3D7_1215900) is a serpentine/G-protein-coupled-like receptor localized to the endoplasmic reticulum of P. falciparum blood stages that regulates intra-erythrocytic developmental cycle duration and coordination with host circadian rhythms; it couples to human Gi/Gq proteins upon binding antimalarial drugs (chloroquine, dihydroartemisinin, piperaquine, primaquine) and the host peptide bradykinin, and its loss impairs asexual replication, disrupts DNA replication and ubiquitin/proteasome pathways, and strongly reduces gametocyte production.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SR10 (PF3D7_1215900) is a serpentine/G-protein-coupled-like receptor of Plasmodium that functions to time and coordinate the intra-erythrocytic developmental cycle (IDC) with host daily rhythms and to sustain both asexual replication and gametocyte production [#0, #1]. SR10 transcription oscillates with a 24 h period, and its genetic disruption in the rodent parasite P. chabaudi shortens the IDC by 2–3 h while perturbing DNA replication and ubiquitin/proteasome pathways, establishing it as a regulator of developmental cycle duration [#0]. In P. falciparum, SR10 is expressed in asexual and sexual blood stages and localizes to the endoplasmic reticulum, where it physically associates with the ER-resident protein ERC; its loss impairs intraerythrocytic replication and strongly reduces gametocyte numbers [#1]. As a receptor, SR10 couples to human Gi/Gq proteins upon activation by antimalarial drugs (chloroquine, dihydroartemisinin, piperaquine-tetraphosphate, primaquine diphosphate) acting as agonists and by the host peptide bradykinin as an endogenous agonist, with ligand-binding sites and activating conformational changes resolved by cryo-EM, mutagenesis, and FlAsH-BRET [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether any parasite factor sets the pace of the intra-erythrocytic cycle and aligns it to host rhythms was unresolved; disruption of SR10 defined it as a timekeeping regulator.\",\n      \"evidence\": \"In vivo loss-of-function disruption in P. chabaudi with transcriptomic and time-series rhythmicity profiling\",\n      \"pmids\": [\"32488076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism linking SR10 to IDC length is not defined\",\n        \"How SR10 impinges on DNA replication and ubiquitin/proteasome pathways is unknown\",\n        \"Rodent-parasite phenotype not directly demonstrated for the IDC-timing role in P. falciparum\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium chabaudi\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The subcellular site of SR10 action and its stage-specific requirement were unknown; localization and disruption studies placed it at the ER and tied it to both replication and sexual commitment.\",\n      \"evidence\": \"Co-localization and reciprocal Co-IP with ER-resident ERC, plus gene disruption scored for replication and gametocyte counts in P. falciparum\",\n      \"pmids\": [\"32890576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the SR10–ERC association is uncharacterized\",\n        \"How an ER-localized receptor controls gametocytogenesis is unresolved\",\n        \"Single-lab evidence for the ER localization\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether SR10 is a bona fide signaling receptor and what activates it were open; structural and biochemical reconstitution established it as a GPCR-like receptor coupling to Gi/Gq and identified drug and peptide agonists.\",\n      \"evidence\": \"Biochemical reconstitution, cryo-EM, mutagenesis, FlAsH-BRET, and proteomic profiling of ligands in P. falciparum\",\n      \"pmids\": [\"41280702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous downstream signaling pathway in the parasite is not mapped\",\n        \"Physiological relevance of bradykinin activation in vivo is not established\",\n        \"Whether drug agonism relates to antimalarial mechanism of action is unaddressed\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ligand binding and Gi/Gq coupling mechanistically connect to IDC timing, ER function, DNA replication, and gametocyte production remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No signaling-to-phenotype causal chain linking receptor activation to developmental control\",\n        \"Native endogenous agonist and its source in the host–parasite context unconfirmed\",\n        \"No integration of the ER localization with GPCR-like signaling model\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031683\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007186\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0048511\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ERC (ER-resident protein, co-IP and co-localization) [#1]\",\n      \"Human Gi/Gq proteins (heterologous coupling partners) [#2]\"\n    ],\n    \"other_free_text\": [\n      \"24 h transcriptional rhythm; disruption shortens the intra-erythrocytic developmental cycle by 2–3 h in P. chabaudi [#0]\",\n      \"Loss disrupts DNA replication and ubiquitin/proteasome pathways [#0]\",\n      \"Disruption impairs intraerythrocytic replication and strongly reduces gametocyte numbers in P. falciparum [#1]\",\n      \"Antimalarial drug agonists: chloroquine, dihydroartemisinin, piperaquine-tetraphosphate, primaquine diphosphate [#2]\",\n      \"Endogenous agonist bradykinin identified by proteomic profiling [#2]\",\n      \"Ligand-binding sites and conformational changes defined by cryo-EM, mutagenesis, and FlAsH-BRET [#2]\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1215900","name":null,"product":"serpentine receptor 10","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1431600","name":null,"product":"serpentine receptor 10, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1435400","name":null,"product":"serpentine receptor 10, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SR10","evaluation":null}