{"uniprot":"Q8N146","gene":"OR8H3","name":"Olfactory receptor 8H3","organism":"Homo sapiens (Human)","status":"dark","length":312,"sequence":"MMGRRNDTNVADFILTGLSDSEEVQMALFMLFLLIYLITMLGNVGMLLIIRLDLQLHTPMYFFLTHLSFIDLSYSTVVTPKTLANLLTSNYISFTGCFAQMFCFVFLGTAECYLLSSMAYDRYAAICSPLHYTVIMPKRLCLALITGPYVIGFMDSFVNVVSMSRLHFCDSNIIHHFFCDTSPILALSCTDTDNTEMLIFIIAGSTLMVSLITISASYVSILSTILKINSTSGKQKAFSTCVSHLLGVTIFYGTMIFTYLKPRKSYSLGRDQVAPVFYTIVIPMLNPLIYSLRNREVKNALIRVMQRRQDSR","function_summary":"A human cell-surface chemosensory receptor that spans the membrane seven times and detects volatile odorants. Ligand binding within its transmembrane pocket triggers conformational changes that activate heterotrimeric G proteins, initiating cyclic-nucleotide signaling cascades that encode smell. Operating at the plasma membrane as a multi-pass receptor, it assembles transient complexes with signaling and regulatory proteins to transduce extracellular chemical cues into intracellular responses that underlie olfactory perception.","plain_language":"OR8H3 has barely been studied. The model's best guess: A human cell-surface chemosensory receptor that spans the membrane seven times and detects volatile odorants. Ligand binding within its transmembrane pocket triggers conformational changes that activate heterotrimeric G proteins, initiating cyclic-nucleotide signaling cascades that encode 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":42,"end":290},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":27,"end":51},{"id":"IPR000725","name":"Olfactory receptor","type":"family","start":32,"end":306},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":60,"end":81},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":104,"end":126},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":272,"end":298}],"reasoning":"I begin with the InterPro architecture. The core transmembrane engine is IPR017452 (GPCR, rhodopsin-like, 7TM domain, residues 42–290), which encodes the canonical seven-helix bundle that transduces extracellular ligand binding into intracellular G-protein activation. This structural core is bracketed and reinforced by multiple rhodopsin-like GPCR family signatures: IPR000276 (G protein-coupled receptor, rhodopsin-like family) appears in the N-terminal region [27–51], the early transmembrane/juxtamembrane region [60–81], and a second internal segment [104–126], and culminates in a C-terminal family motif [272–298]. These distributed family hits collectively specify a class A GPCR scaffold that couples to heterotrimeric G proteins. Superimposed on this scaffold, IPR000725 (Olfactory receptor family, residues 32–306) assigns the receptor to the olfactory clade of class A GPCRs, whose extracellular N-termini and transmembrane pocket bind volatile odorant molecules and whose intracellular loops engage the olfactory G protein. The ordered layout—an N-terminal olfactory signature feeding into a rhodopsin-like 7TM core and reinforced by conserved intracellular loop motifs—causally dictates G-protein coupling and signal initiation.\n\nFrom this architecture, the molecular function follows. The seven-helix bundle and conserved rhodopsin-like motifs create a ligand-gated allosteric switch that binds intracellular partners; this necessitates multivalent protein interactions consistent with GO:0005515 protein binding. The binding event triggers conformational changes that catalyze GDP-GTP exchange on Gα subunits, a hallmark of GPCR signaling.\n\nThis GPCR activity drives the biological process layer. Activation of heterotrimeric G proteins defines GO:0007186 G protein-coupled receptor signaling pathway. Because the receptor belongs to the olfactory family and is tuned to odorants, its signaling specifically implements GO:0007608 sensory perception of smell. The causal chain is direct: odorant occupancy in the 7TM pocket reshapes the intracellular face, activates G proteins, and initiates downstream second-messenger cascades that encode olfactory information.\n\nCellular location is dictated by the 7TM architecture and the need to sample extracellular odorants. The hydrophobic helical bundle embeds the protein as a multi-pass membrane receptor at the cell surface, aligning with GO:0005886 plasma membrane and the experimentally supported designation as a cell membrane, multi-pass membrane protein. This placement ensures cytosolic exposure of G-protein coupling loops and extracellular access to small-molecule ligands.\n\nMechanistically, I hypothesize that the receptor binds a subset of hydrophobic odorants within the transmembrane pocket, stabilizing an active state that recruits and activates the olfactory G protein (Golf). G protein activation then stimulates adenylyl cyclase to raise cAMP, opening cyclic nucleotide-gated channels and depolarizing the neuron. The receptor likely cycles via GRK-mediated phosphorylation and β-arrestin binding to terminate signaling and traffic through endocytic pathways. Thus, its principal partners are heterotrimeric G proteins, GPCR kinases, and arrestins, with accessory chaperones facilitating membrane delivery and functional tuning.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8N146.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8N146"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8N146/entry","atlas":"/p/Q8N146"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}