{"uniprot":"Q8NGN0","gene":"OR4D5","name":"Olfactory receptor 4D5","organism":"Homo sapiens (Human)","status":"dark","length":318,"sequence":"MNPANHSQVAGFVLLGLSQVWELRFVFFTVFSAVYFMTVVGNLLIVVIVTSDPHLHTTMYFLLGNLSFLDFCYSSITAPRMLVDLLSGNPTISFGGCLTQLFFFHFIGGIKIFLLTVMAYDRYIAISQPLHYTLIMNQTVCALLMAASWVGGFIHSIVQIALTIQLPFCGPDKLDNFYCDVPQLIKLACTDTFVLELLMVSNNGLVTLMCFLVLLGSYTALLVMLRSHSREGRSKALSTCASHIAVVTLIFVPCIYVYTRPFRTFPMDKAVSVLYTIVTPMLNPAIYTLRNKEVIMAMKKLWRRKKDPIGPLEHRPLH","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 that converts chemical cues into neuronal activity underlying smell. Its multi-pass topology anchors it at the plasma membrane, where it binds signaling partners, couples to cyclic nucleotide pathways, and undergoes regulation by phosphorylation and arrestin-mediated desensitization.","plain_language":"OR4D5 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 that converts chemical cues into neuronal activity underlying 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":41,"end":287},{"id":"IPR050427","name":"Human Olfactory Receptors","type":"family","start":6,"end":305},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":26,"end":50},{"id":"IPR000725","name":"Olfactory receptor","type":"family","start":31,"end":302},{"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":269,"end":295}],"reasoning":"I begin with the InterPro architecture. The core transmembrane engine is IPR017452 (GPCR, rhodopsin-like, 7TM domain, residues 41–287), which encodes the canonical seven-helix bundle that transduces extracellular ligand binding into intracellular G-protein activation. This structural core is embedded within multiple olfactory/GPCR family signatures that frame the entire polypeptide: IPR050427 (Human Olfactory Receptors family, residues 6–305) and IPR000725 (Olfactory receptor family, residues 31–302) define the receptor as a member of the vertebrate olfactory GPCR clade. Three rhodopsin-like GPCR family annotations punctuate the sequence—IPR000276 (G protein-coupled receptor, rhodopsin-like family, residues 26–50), IPR000276 (residues 104–126), and IPR000276 (residues 269–295)—marking conserved motifs that stabilize the inactive and active states and couple to heterotrimeric G proteins. The ordered layout—N-terminal extracellular region, followed by the 7TM bundle and intracellular C-terminus—creates a signal-transducing module that binds small hydrophobic ligands in the transmembrane cavity and transmits conformational changes to cytosolic G-protein interfaces.\n\nThis architecture dictates molecular function. The rhodopsin-like 7TM fold and olfactory receptor family signatures cause G protein-coupled receptor activity that detects volatile chemicals and activates downstream effectors. The intracellular loops and C-terminal tail serve as docking surfaces for heterotrimeric G proteins and other signaling partners, which substantiates GO:0005515 protein binding as an intrinsic property of this receptor’s signaling cycle.\n\nFrom function to process, the coupling of extracellular odorant recognition to intracellular G-protein activation places the receptor squarely in GO:0007186 G protein-coupled receptor signaling pathway. In olfactory neurons, this signaling initiates cyclic nucleotide cascades that encode odor information, thereby driving GO:0007608 sensory perception of smell. The causal chain is direct: ligand binding within the 7TM cavity triggers G-protein exchange and second-messenger production, which converts a chemical cue into an electrical signal.\n\nCellular location follows from the fold and topology. The seven-pass bundle and olfactory receptor family membership necessitate insertion into the lipid bilayer as a multi-pass membrane protein. This supports a residence at the GO:0005886 plasma membrane, consistent with a cell-surface receptor that samples the extracellular milieu and signals inward.\n\nMechanistically, the receptor likely binds hydrophobic odorants within the transmembrane pocket, stabilizing an active conformation that opens the intracellular G-protein interface. In olfactory neurons, this conformation preferentially engages the olfactory G protein (Golf), stimulating adenylyl cyclase and elevating cAMP to open cyclic nucleotide-gated channels. The receptor’s cytosolic tail and intracellular loops mediate transient protein binding to Gα/β/γ, GRKs, and arrestins, shaping both signal amplitude and desensitization. I therefore hypothesize interactions with Golf (GNAL), Gβγ subunits, adenylyl cyclase 3, receptor-transporting proteins (RTP/REEP) that chaperone trafficking to the plasma membrane, and arrestin/GRK modules that terminate signaling and direct internalization.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8NGN0.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8NGN0"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8NGN0/entry","atlas":"/p/Q8NGN0"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}