Diagrammatic representation of different classes of allosteric sites and exemplar ligands of LGICs. ECD, extracellular domain; TMD, transmembrane domain; CD, cytoplasmic domain.

Crystal structures of ligand-gated ion channels, showing the range of allosteric (or coagonist) binding sites. (A) Ethanol binding sites on the ethanol-sensitive mutant GLIC pentameric ligand gated ion channel (PDB ID 4HFE). (B) Ketamine bound to the GLIC pentameric ligand gated ion channel (PDB ID 4F8H). (C) GluN1/GluN2A ligand-binding domain in complex with GluN receptor coagonists glycine and glutamate (PDB ID 4NF8). (D) Crystal structure of amino terminal domains of the GluN receptor subunit GluN1 and GluN2B in complex with ifenprodil (PDB ID 3QEL). Crystal structure of a pentameric ligand gated ion channel Erminia ligand-gated ion channel in complex with GABA and flurazepam (E; PDB ID 2YOE) or zopiclone (F; PDB ID 4A97).

(A) Side view of the crystal structure of the bacterial Na_VAb VGIC (Payandeh et al., 2011). (Left) Na_VAb crystal structure illustrating the voltage-sensing module (green), pore module (blue), and connecting S4–S5 linker (red) in the preopen state. (Right) The Na_vAb pore module in the preopen state, indicating amino acids implicated in the binding of channel pore blockers. The tight closure in the intracellular regions provides a structural explanation for use-dependent blockade by large or hydrophilic drugs, because they would bind more rapidly upon channel opening. The amino acid Phe203 plays a key role in governing drug access to this site. The other highlighted residues, Thr206 (blue), Met209 (green), and Val213 (orange) have been implicated as key contributors to the drug-binding pocket in mammalian Na_V channels. (B) Diagrammatic representation of multiple distinct allosteric sites for neurotoxins and local anesthetics at voltage-gated sodium channels, with exemplar molecules listed. The channels comprise four homologous voltage-sensing domains (I–IV), each composed of six (S1–S6) segments, which surround a central pore. The locations of the different allosteric sites (Site 1–6 and the local anesthetic site) are indicated both with regards to their domain location (left) and their localization within a given intradomain module (right). TTX, tetrodotoxin; STX, saxitoxin.

Topographically distinct but conformationally linked domains within GPCRs. (A) Structures of the chemokine CCR5 receptor bound to maraviroc (PDB ID 4MBS) and the corticotrophin releasing factor receptor (CRF1) bound to CP-376395 (PDB ID 4K5Y). (B) Structure of the M₂ mAChR (PDB ID 4MQT) in complex with a positive allosteric modulator (LY02119620, purple), an agonist (iperoxo, yellow), and a nanobody (Nb9-8, green) that stabilizes an active state of the receptor.

(A) Modular domain structure of NHRs. (B) Crystal structure of the PPARγ/RXR heterodimeric NHR (PDB ID 3DZY) bound to the orthosteric ligands retinoic acid and rosiglitazone, highlighting potential sites for allosteric modulation. AF, activation function.

(A) Schematic representation of the allosteric transition mechanism proposed for intact epidermal growth factor receptor activation based on long timescale molecular dynamics simulations. EC, extracellular; JM, juxtramembrane. Transition from inactive to active states involves ligand-dependent reorientation of the C- versus N-terminal ends of the TM region. (B) Three-dimensional representation of the 4.2-Å crystal structure of the FGF receptor 2 (FGFR2) extracellular D2–D3 region in complex with FGF1 in the absence (left) or presence (right) of the allosteric modulator SSR1281129E (SSR). Although the molecule could not be resolved at this resolution, the change in B factors (which quantify changes in the vibrational motions of different parts of a structure) suggests an increase in the flexibility of the D3 region. The inset shows a predicted binding mode for the modulator in the D3 region based on free energy calculations and in silico docking. Reproduced, with permission, from Herbert et al. (2013).