{"gene":"PF3D7_1146600","run_date":"2026-09-08T14:19:05","timeline":{"discoveries":[{"year":2016,"finding":"ORP1 (PF3D7_1146600) contains a histone-fold domain (HFD) that promotes heterodimer formation with ORP2 at the oocyst capsule. Loss of ORP1 prevents oocyst rupture, and mutational analysis confirmed the HFD is essential for ORP1 function. Heterodimer formation between ORP1 and ORP2 was verified in vitro.","method":"Genetic knockout (loss-of-function), mutational analysis of HFD, in vitro heterodimer reconstitution","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of heterodimer, mutagenesis confirming HFD essentiality, and clean loss-of-function phenotype, all in one study","pmids":["27982038"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"ORP1 (PF3D7_1146600) localizes to the oocyst capsule at the time of rupture, placing it structurally at the site where it functions in sporozoite release.","method":"Protein localization (immunofluorescence/imaging at oocyst capsule)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization described in abstract without detailed method specification, but consistent with functional phenotype in the same paper","pmids":["27982038"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2026,"finding":"The X-ray crystal structure of the ORP1/ORP2 HFD heterodimer was solved at 3.1 Å resolution, revealing the dimerization interface. Six cyclic peptides identified by a GAL4-based yeast two-hybrid combinatorial library were shown to inhibit ORP1–ORP2 dimerization in vitro, with molecular docking confirming binding at the dimer interface.","method":"X-ray crystallography (3.1 Å), GAL4-based yeast two-hybrid cyclic peptide screen, in vitro dimerization inhibition assay, molecular docking","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation of interface by in vitro inhibition assays and docking, single study but multiple orthogonal methods","pmids":["41506730"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2026,"finding":"ORP1 (PF3D7_1146600) forms a trimeric complex with ORP2 and a newly identified protein ORP3, analogous to the NF-Y transcription factor complex. The ORP1/ORP2 dimer recruits ORP3 via the conserved NF-YA helix A1 of ORP3, and trimeric complex formation was confirmed in vitro using a yeast three-hybrid approach. This trimeric complex is essential for oocyst capsule excystation and sporozoite egress.","method":"Yeast three-hybrid (Y3H) in vitro complex formation, genetic knockout of ORP3 with phenotypic analysis of oocyst rupture, deletion mutagenesis of ORP3 helix A1","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro trimeric complex reconstitution by Y3H, mutagenesis confirming helix A1 essentiality, and clean loss-of-function phenotype, single study with multiple orthogonal methods","pmids":["42045549"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"ORP1 (PF3D7_1146600) is an oocyst capsule-localized protein whose histone-fold domain (HFD) is essential for forming a heterodimer with ORP2 and, together with a third subunit ORP3, assembles into a trimeric NF-Y-like complex at the oocyst capsule; this complex is required for oocyst rupture and sporozoite egress into the mosquito salivary glands, and the HFD dimerization interface has been structurally resolved at 3.1 Å and shown to be pharmacologically targetable."},"narrative":{"mechanistic_narrative":"ORP1 (PF3D7_1146600) is an oocyst capsule protein required for sporozoite egress during the mosquito stage of the Plasmodium life cycle, characterized in the P. berghei ortholog [PMID:27982038]. It carries a histone-fold domain (HFD) that mediates heterodimer formation with ORP2, and this HFD is essential for ORP1 function: its loss blocks oocyst rupture [PMID:27982038]. The X-ray crystal structure of the ORP1/ORP2 HFD heterodimer, solved at 3.1 Å, defines the dimerization interface, which is pharmacologically targetable by cyclic peptides that inhibit ORP1–ORP2 dimerization in vitro [PMID:41506730]. The ORP1/ORP2 dimer further recruits a third subunit, ORP3, through the conserved NF-YA helix A1 of ORP3, assembling a trimeric NF-Y-like complex that is essential for oocyst capsule excystation and sporozoite egress [PMID:42045549]. Beyond its assembly into this capsule-localized complex and its role in oocyst rupture, no additional molecular activity for ORP1 has been characterized in the available corpus.","teleology":[{"year":2016,"claim":"Establishing whether ORP1 has a defined role in the mosquito stage, this work showed its histone-fold domain drives heterodimerization with ORP2 and is required for oocyst rupture, defining ORP1 as an egress factor rather than an uncharacterized ORF.","evidence":"Genetic knockout, HFD mutational analysis, and in vitro heterodimer reconstitution in P. berghei","pmids":["27982038"],"confidence":"High","gaps":["Does not resolve the atomic geometry of the ORP1/ORP2 interface","Mechanism by which the dimer triggers capsule rupture is unspecified","Whether additional subunits participate is not addressed"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"claim":"To place ORP1 at the site of its function, imaging localized it to the oocyst capsule at the time of rupture, linking the biochemical activity to a defined subcellular structure.","evidence":"Protein localization imaging at the oocyst capsule in P. berghei","pmids":["27982038"],"confidence":"Medium","gaps":["Localization method not detailed in the abstract","Does not establish how ORP1 is targeted to the capsule"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2026,"claim":"To define the interface at atomic resolution and test its druggability, the ORP1/ORP2 HFD heterodimer structure was solved at 3.1 Å and cyclic peptides were shown to inhibit dimerization, demonstrating the interface is a targetable node.","evidence":"X-ray crystallography, GAL4 yeast two-hybrid cyclic peptide screen, in vitro dimerization inhibition, and molecular docking in P. berghei","pmids":["41506730"],"confidence":"High","gaps":["In vitro inhibition not yet shown to block oocyst rupture in vivo","Selectivity of the cyclic peptides against host complexes not addressed"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2026,"claim":"Extending the dimer to a higher-order assembly, ORP1/ORP2 were shown to recruit ORP3 via the NF-YA helix A1 to form a trimeric NF-Y-like complex essential for excystation, revealing the functional unit is a trimer.","evidence":"Yeast three-hybrid reconstitution, ORP3 knockout with oocyst rupture phenotyping, and ORP3 helix A1 deletion mutagenesis in P. berghei","pmids":["42045549"],"confidence":"High","gaps":["Whether the trimer acts as a transcription factor or via a non-transcriptional role at the capsule is not established","Downstream effectors of rupture are unidentified","Stoichiometry and dynamics in vivo not resolved"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"The biochemical mechanism by which the ORP1/ORP2/ORP3 trimeric complex executes oocyst capsule rupture, and whether the P. falciparum ortholog behaves identically to the P. berghei protein, remain open.","evidence":"No timeline discovery addresses the effector mechanism of rupture or the P. falciparum ortholog directly","pmids":[],"confidence":"Low","gaps":["No downstream target or enzymatic output of the complex identified","Function characterized only in P. berghei ortholog, not in P. falciparum PF3D7_1146600 itself","Regulation of complex assembly timing relative to rupture unknown"],"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["ORP1/ORP2 HFD heterodimer","ORP1/ORP2/ORP3 trimeric NF-Y-like complex"],"partners":["ORP2","ORP3"],"other_free_text":["Histone-fold domain (HFD) is essential for ORP1 function and mediates ORP2 heterodimerization [#0]","ORP1/ORP2 dimerization interface resolved at 3.1 Å and inhibited by cyclic peptides in vitro [#2]","ORP3 is recruited to the ORP1/ORP2 dimer via its conserved NF-YA helix A1 [#3]","All functional characterization to date is in the Plasmodium berghei ortholog"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"27982038","id":"PMC_27982038","title":"Release of Plasmodium sporozoites requires proteins with histone-fold dimerization domains.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27982038","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ORP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30391497","id":"PMC_30391497","title":"Identification of Plasmodium berghei Oocyst Rupture Protein 2 (ORP2) domains involved in sporozoite egress from the oocyst.","date":"2018","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/30391497","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ORP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41506730","id":"PMC_41506730","title":"Targeting the histone-fold dimerization interface of oocyst rupture proteins from Plasmodium berghei for antimalarial inhibitor discovery.","date":"2026","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/41506730","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ORP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42045549","id":"PMC_42045549","title":"Sporozoite egress from Plasmodium oocysts requires a trimeric NF-Y-like complex.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/42045549","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ORP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4711,"output_tokens":1262,"usd":0.016532,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6116,"output_tokens":2372,"usd":0.04494,"stage2_stop_reason":"end_turn"},"total_usd":0.061472,"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\": 2016,\n      \"finding\": \"ORP1 (PF3D7_1146600) contains a histone-fold domain (HFD) that promotes heterodimer formation with ORP2 at the oocyst capsule. Loss of ORP1 prevents oocyst rupture, and mutational analysis confirmed the HFD is essential for ORP1 function. Heterodimer formation between ORP1 and ORP2 was verified in vitro.\",\n      \"method\": \"Genetic knockout (loss-of-function), mutational analysis of HFD, in vitro heterodimer reconstitution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of heterodimer, mutagenesis confirming HFD essentiality, and clean loss-of-function phenotype, all in one study\",\n      \"pmids\": [\"27982038\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ORP1 (PF3D7_1146600) localizes to the oocyst capsule at the time of rupture, placing it structurally at the site where it functions in sporozoite release.\",\n      \"method\": \"Protein localization (immunofluorescence/imaging at oocyst capsule)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization described in abstract without detailed method specification, but consistent with functional phenotype in the same paper\",\n      \"pmids\": [\"27982038\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The X-ray crystal structure of the ORP1/ORP2 HFD heterodimer was solved at 3.1 Å resolution, revealing the dimerization interface. Six cyclic peptides identified by a GAL4-based yeast two-hybrid combinatorial library were shown to inhibit ORP1–ORP2 dimerization in vitro, with molecular docking confirming binding at the dimer interface.\",\n      \"method\": \"X-ray crystallography (3.1 Å), GAL4-based yeast two-hybrid cyclic peptide screen, in vitro dimerization inhibition assay, molecular docking\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation of interface by in vitro inhibition assays and docking, single study but multiple orthogonal methods\",\n      \"pmids\": [\"41506730\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ORP1 (PF3D7_1146600) forms a trimeric complex with ORP2 and a newly identified protein ORP3, analogous to the NF-Y transcription factor complex. The ORP1/ORP2 dimer recruits ORP3 via the conserved NF-YA helix A1 of ORP3, and trimeric complex formation was confirmed in vitro using a yeast three-hybrid approach. This trimeric complex is essential for oocyst capsule excystation and sporozoite egress.\",\n      \"method\": \"Yeast three-hybrid (Y3H) in vitro complex formation, genetic knockout of ORP3 with phenotypic analysis of oocyst rupture, deletion mutagenesis of ORP3 helix A1\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro trimeric complex reconstitution by Y3H, mutagenesis confirming helix A1 essentiality, and clean loss-of-function phenotype, single study with multiple orthogonal methods\",\n      \"pmids\": [\"42045549\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"ORP1 (PF3D7_1146600) is an oocyst capsule-localized protein whose histone-fold domain (HFD) is essential for forming a heterodimer with ORP2 and, together with a third subunit ORP3, assembles into a trimeric NF-Y-like complex at the oocyst capsule; this complex is required for oocyst rupture and sporozoite egress into the mosquito salivary glands, and the HFD dimerization interface has been structurally resolved at 3.1 Å and shown to be pharmacologically targetable.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ORP1 (PF3D7_1146600) is an oocyst capsule protein required for sporozoite egress during the mosquito stage of the Plasmodium life cycle, characterized in the P. berghei ortholog [#0, #1]. It carries a histone-fold domain (HFD) that mediates heterodimer formation with ORP2, and this HFD is essential for ORP1 function: its loss blocks oocyst rupture [#0]. The X-ray crystal structure of the ORP1/ORP2 HFD heterodimer, solved at 3.1 Å, defines the dimerization interface, which is pharmacologically targetable by cyclic peptides that inhibit ORP1–ORP2 dimerization in vitro [#2]. The ORP1/ORP2 dimer further recruits a third subunit, ORP3, through the conserved NF-YA helix A1 of ORP3, assembling a trimeric NF-Y-like complex that is essential for oocyst capsule excystation and sporozoite egress [#3]. Beyond its assembly into this capsule-localized complex and its role in oocyst rupture, no additional molecular activity for ORP1 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing whether ORP1 has a defined role in the mosquito stage, this work showed its histone-fold domain drives heterodimerization with ORP2 and is required for oocyst rupture, defining ORP1 as an egress factor rather than an uncharacterized ORF.\",\n      \"evidence\": \"Genetic knockout, HFD mutational analysis, and in vitro heterodimer reconstitution in P. berghei\",\n      \"pmids\": [\"27982038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve the atomic geometry of the ORP1/ORP2 interface\",\n        \"Mechanism by which the dimer triggers capsule rupture is unspecified\",\n        \"Whether additional subunits participate is not addressed\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To place ORP1 at the site of its function, imaging localized it to the oocyst capsule at the time of rupture, linking the biochemical activity to a defined subcellular structure.\",\n      \"evidence\": \"Protein localization imaging at the oocyst capsule in P. berghei\",\n      \"pmids\": [\"27982038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Localization method not detailed in the abstract\",\n        \"Does not establish how ORP1 is targeted to the capsule\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"To define the interface at atomic resolution and test its druggability, the ORP1/ORP2 HFD heterodimer structure was solved at 3.1 Å and cyclic peptides were shown to inhibit dimerization, demonstrating the interface is a targetable node.\",\n      \"evidence\": \"X-ray crystallography, GAL4 yeast two-hybrid cyclic peptide screen, in vitro dimerization inhibition, and molecular docking in P. berghei\",\n      \"pmids\": [\"41506730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vitro inhibition not yet shown to block oocyst rupture in vivo\",\n        \"Selectivity of the cyclic peptides against host complexes not addressed\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extending the dimer to a higher-order assembly, ORP1/ORP2 were shown to recruit ORP3 via the NF-YA helix A1 to form a trimeric NF-Y-like complex essential for excystation, revealing the functional unit is a trimer.\",\n      \"evidence\": \"Yeast three-hybrid reconstitution, ORP3 knockout with oocyst rupture phenotyping, and ORP3 helix A1 deletion mutagenesis in P. berghei\",\n      \"pmids\": [\"42045549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the trimer acts as a transcription factor or via a non-transcriptional role at the capsule is not established\",\n        \"Downstream effectors of rupture are unidentified\",\n        \"Stoichiometry and dynamics in vivo not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which the ORP1/ORP2/ORP3 trimeric complex executes oocyst capsule rupture, and whether the P. falciparum ortholog behaves identically to the P. berghei protein, remain open.\",\n      \"evidence\": \"No timeline discovery addresses the effector mechanism of rupture or the P. falciparum ortholog directly\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No downstream target or enzymatic output of the complex identified\",\n        \"Function characterized only in P. berghei ortholog, not in P. falciparum PF3D7_1146600 itself\",\n        \"Regulation of complex assembly timing relative to rupture unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"protein heterodimerization activity\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"protein-containing complex assembly\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"oocyst capsule\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"sporozoite egress / oocyst rupture\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\n      \"ORP1/ORP2 HFD heterodimer\",\n      \"ORP1/ORP2/ORP3 trimeric NF-Y-like complex\"\n    ],\n    \"partners\": [\n      \"ORP2\",\n      \"ORP3\"\n    ],\n    \"other_free_text\": [\n      \"Histone-fold domain (HFD) is essential for ORP1 function and mediates ORP2 heterodimerization [#0]\",\n      \"ORP1/ORP2 dimerization interface resolved at 3.1 Å and inhibited by cyclic peptides in vitro [#2]\",\n      \"ORP3 is recruited to the ORP1/ORP2 dimer via its conserved NF-YA helix A1 [#3]\",\n      \"All functional characterization to date is in the Plasmodium berghei ortholog\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1146600","name":null,"product":"oocyst rupture protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"Pf3D7","gene_id":"PF3D7_1146700","name":null,"product":"kinesin-X4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0902400","name":null,"product":"kinesin-X4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0902500","name":null,"product":"oocyst rupture protein 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0944400","name":null,"product":"oocyst rupture protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0944500","name":null,"product":"kinesin-X4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ORP1","evaluation":null}