{"uniprot":"Q8NGP6","gene":"OR5M8","name":"Olfactory receptor 5M8","organism":"Homo sapiens (Human)","status":"dark","length":311,"sequence":"MRRNCTLVTEFILLGLTSRRELQILLFTLFLAIYMVTVAGNLGMIVLIQANAWLHMPMYFFLSHLSFVDLCFSSNVTPKMLEIFLSEKKSISYPACLVQCYLFIALVHVEIYILAVMAFDRYMAICNPLLYGSRMSKSVCSFLITVPYVYGALTGLMETMWTYNLAFCGPNEINHFYCADPPLIKLACSDTYNKELSMFIVAGWNLSFSLFIICISYLYIFPAILKIRSTEGRQKAFSTCGSHLTAVTIFYATLFFMYLRPPSKESVEQGKMVAVFYTTVIPMLNLIIYSLRNKNVKEALIKELSMKIYFS","function_summary":"A seven-helix membrane chemosensor that detects volatile odorants and initiates a G protein–mediated signaling cascade at the cell surface. Ligand binding within a transmembrane pocket shifts the receptor into an active conformation that engages heterotrimeric G proteins, elevates cyclic nucleotide signaling, and drives neuronal responses underlying the sense of smell. Its multi-pass architecture anchors it in the plasma membrane, where it assembles with signaling and regulatory partners to transduce extracellular chemical cues into intracellular signals.","plain_language":"OR5M8 has barely been studied. The model's best guess: A seven-helix membrane chemosensor that detects volatile odorants and initiates a G protein–mediated signaling cascade at the cell surface. Ligand binding within a transmembrane pocket shifts the receptor into an active conformation that engages heterotrimeric G proteins, elevates cyclic nucleotide signaling, and drives neuronal responses underlying the sense of smell.","uniprot_summary":"Odorant receptor.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0007186","label":"G protein-coupled receptor signaling pathway"},{"id":"GO:0007608","label":"sensory perception of smell"}],"cellular_component":[{"id":"GO:0005886","label":"plasma membrane"}]},"interpro":[{"id":"IPR017452","name":"GPCR, rhodopsin-like, 7TM","type":"domain","start":40,"end":289},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":25,"end":49},{"id":"IPR000725","name":"Olfactory receptor","type":"family","start":30,"end":306},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":58,"end":79},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":103,"end":125},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":271,"end":297}],"reasoning":"I begin with the InterPro architecture. The core transmembrane engine is IPR017452 (GPCR, rhodopsin-like, 7TM domain, residues 40–289), which encodes the canonical seven-helix bundle that transduces extracellular ligand binding into intracellular G-protein activation. This structural core is embedded within multiple rhodopsin-like GPCR family signatures: IPR000276 (G protein-coupled receptor, rhodopsin-like family) appears in the N-terminal region [25–49], mid-loop region [58–79], and the distal transmembrane-proximal region [271–297], and a third family signature sits within the central helix bundle [103–125]. Together, these overlapping family assignments specify a class A GPCR scaffold that couples to heterotrimeric G proteins. Superimposed on this scaffold, IPR000725 (Olfactory receptor family, residues 30–306) defines the receptor subclass that recognizes volatile odorants. The ordered layout—an N-terminal extracellular region feeding into a 7TM rhodopsin-like core and terminating with intracellular coupling loops—causally establishes a receptor that binds small hydrophobic ligands in a membrane-embedded pocket and transduces that binding into G-protein signaling.\n\nFrom this architecture, the molecular function follows. The rhodopsin-like 7TM fold and olfactory receptor family identity dictate GPCR-mediated signal initiation. The intracellular loops and C-terminal tail of class A GPCRs form selective interfaces for heterotrimeric Gα/βγ and accessory proteins, which necessitates multivalent protein binding; this supports GO:0005515 protein binding as a basal capability intrinsic to receptor coupling and scaffolding.\n\nThe biological process emerges directly from the signaling logic. A rhodopsin-like olfactory receptor triggers the canonical GPCR cascade (activation of Gα and dissociation of Gβγ), situating the protein squarely in GO:0007186 G protein-coupled receptor signaling pathway. Because the receptor class specializes in detecting environmental odorants and converting that detection into intracellular signaling, it drives GO:0007608 sensory perception of smell. The causal chain is: a hydrophobic odorant binds within the 7TM pocket; this conformational change activates G proteins; downstream effectors (e.g., adenylyl cyclase and cyclic nucleotide signaling) produce neuronal depolarization.\n\nCellular location is dictated by the 7TM architecture and the need to access extracellular odorants. The multi-pass topology and signal-transduction role require insertion into the lipid bilayer, and the functional context of odor detection places the receptor at the cell surface. This supports GO:0005886 plasma membrane and aligns with a multi-pass membrane protein topology.\n\nMechanistically, the receptor likely operates through the olfactory transduction pathway. Upon odorant binding, the receptor stabilizes an active state that recruits and activates Golf (a Gα subtype), releasing Gβγ to stimulate adenylyl cyclase III and elevate cAMP. This second messenger opens cyclic nucleotide-gated channels and amplifies the signal. The receptor’s cytosolic face and C-terminal motifs provide the binding surfaces that mediate assembly with G proteins and regulatory partners, explaining its strong protein-binding propensity and its precise membrane localization.\n\nFrom this mechanism, I hypothesize interaction partners that fit the architecture and pathway: heterotrimeric G proteins (GNAL/Golf, Gβγ), adenylyl cyclase 3, receptor-transport and trafficking factors that chaperone olfactory receptors to the membrane, and arrestin/GRK modules that terminate signaling. These associations collectively ensure efficient odorant detection and tightly regulated GPCR signaling at the plasma membrane.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8NGP6.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8NGP6"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8NGP6/entry","atlas":"/p/Q8NGP6"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}