GPCR biology & structural anatomy
G protein-coupled receptors are the cell's universal signal detectors. A single fold — seven membrane-spanning helices — has been tuned by evolution to sense photons, ions, small molecules, peptides, and whole proteins, and to relay that signal across the membrane. This page is a short primer on how they are built, how they work, and how drugs act on them.
What is a GPCR?
GPCRs — also called seven-transmembrane (7TM) receptors — are the largest family of membrane proteins in the human genome, with roughly 800 members. About half detect odours and tastes; the other ~400 respond to hormones, neurotransmitters, and other signalling molecules, and it is these that dominate as drug targets. Roughly a third of all approved medicines act through a GPCR.
Every GPCR shares the same core architecture: an extracellular face that recognises the signal, seven α-helices that cross the membrane, and an intracellular face that couples to signalling machinery — most famously the heterotrimeric G proteins that give the family its name.
Structure & function at a glance
GPCR · Structure & Function
G protein-coupled receptors are seven-transmembrane (7-TM) receptors that sense extracellular signals and activate heterotrimeric G proteins to initiate intracellular signalling cascades.
- Seven transmembrane (7-TM) helices span the membrane
- Orthosteric pocket binds the natural (endogenous) ligand
- Allosteric pocket binds modulators away from the main site
- Couples to heterotrimeric G proteins (α, β, γ)
- Intracellular loops interact with the G protein
- C-terminal tail is phosphorylated and recruits β-arrestin
Without a ligand, the receptor rests in an inactive conformation. The G protein is bound to GDP and stays associated with the receptor.
An extracellular ligand binds the orthosteric pocket, stabilising the active conformation of the receptor.
Binding triggers a structural rearrangement that lets the intracellular loops engage the G protein and promote GDP release from Gα.
Gα exchanges GDP for GTP and dissociates from βγ. Both Gα-GTP and βγ regulate downstream effectors. GRKs phosphorylate the C-terminal tail.
G-protein and β-arrestin pathways can be engaged to different extents, producing distinct signalling outputs — biased signalling.
GPCR residue numbering
GPCRs of the same class share a common seven-helix fold but differ widely in length, so a raw sequence position (e.g. “Arg135”) means something different in every receptor. To talk about equivalent positions across the family, GPCR pharmacology uses a generic residue-numbering scheme that indexes a residue by its transmembrane helix and its position relative to the most conserved residue in that helix.
The first number is the transmembrane helix (1–7). The second is the residue’s position within that helix, where the most conserved residue is assigned .50. Positions count down toward the N-terminus (…, 3.49, 3.48) and up toward the C-terminus (3.51, 3.52, …). So 3.50 denotes the conserved arginine of the D[E]RY motif in every class A receptor, whatever its absolute residue number.
| Position | Residue | Landmark |
|---|---|---|
| 1.50 | Asn (N) | Anchor of TM1 |
| 2.50 | Asp (D) | Sodium-pocket aspartate |
| 3.50 | Arg (R) | Arginine of the D[E]RY motif |
| 4.50 | Trp (W) | Buried tryptophan of TM4 |
| 5.50 | Pro (P) | Proline kink in TM5 |
| 6.50 | Pro (P) | Proline of the CWxP motif |
| 7.50 | Pro (P) | Proline of the NPxxY motif |
GPCRdb structure-based numbering
Real helices contain bulges and constrictions, so the sequence-based position can drift out of structural register. GPCRdb therefore adds a second, structure-based index — written after an x, as in 3.50x50. The part before the x is the classic (sequence) number; the part after it is aligned to a common structural reference, keeping equivalent 3D positions in step even where a helix inserts or deletes a residue. Loop residues use an analogous scheme keyed to the flanking helices (e.g. ECL2, ICL3).
Class-specific schemes
Each GPCR class has its own historical numbering, all built on the same “.50 = most conserved” idea. GPCRdb unifies them under one structure-based generic numbering so positions can be compared across classes.
Helix7 stores GPCRdb generic numbering with each receptor, so a residue such as 6.48 (the “toggle switch” tryptophan) or 3.50 can be located in any receptor and compared across the family.
Mechanisms of pharmacological action
Drugs are classified by what they do to the receptor, not merely whether they bind. Two properties define the behaviour: affinity (how tightly a ligand binds) and efficacy (how much it changes activity once bound). Toggle each class below to see how it reshapes the dose–response curve.
Orthosteric vs allosteric
Orthosteric ligands compete for the endogenous agonist's pocket. Allosteric modulators bind elsewhere and tune the response — positive (PAM) or negative (NAM) — often with greater selectivity because allosteric sites are less conserved across a receptor family.
Competitive vs insurmountable
A competitive antagonist shifts the agonist curve rightward and can be overcome by more agonist. An insurmountable (irreversible or pseudo-irreversible) antagonist also lowers the maximum response.
Constitutive activity
Some receptors signal even without a ligand. Only against this basal tone can an inverse agonist show its effect — actively turning activity down rather than merely blocking it.
Biased agonism
A biased (functionally selective) agonist stabilises a conformation that favours one downstream pathway — say β-arrestin over Gᵢ — an active area of drug design aimed at cleaner therapeutics.