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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Crystal structure of a human GABAA receptor Paul S. Miller , A. Radu Aricescu Nature 512 (7514), 270 - 275 DOI: 10.1038/nature13293 PMID: 24909990 Diamond Proposal Number(s): [8423] Open Access Show Abstract ▼ Abstract: Type-A ?-aminobutyric acid receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABAAR, the human ?3 homopentamer, at 3?Å resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABAAR modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission.	Aug 2014
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structural basis for GABAA receptor potentiation by neurosteroids Paul S. Miller , Suzanne Scott , Simonas Masiulis , Luigi De Colibus , Els Pardon , Jan Steyaert , A Radu Aricescu Nature Structural & Molecular Biology 90 DOI: 10.1038/nsmb.3484 Diamond Proposal Number(s): [10627] Show Abstract ▼ Abstract: Type A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABAARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain unknown. Here we report crystal structures of a chimeric GABAAR construct in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore and modulates the desensitization-gate conformation. We demonstrate that the equivalent site is responsible for physiological, heteromeric GABAAR potentiation and explain the contrasting modulatory properties of 3a versus 3b neurosteroid epimers. These results illustrate how peripheral lipid ligands can regulate the desensitization gate of GABAARs, a process of broad relevance to pentameric ligand-gated ion channels.	Oct 2017
B21-High Throughput SAXS I24-Microfocus Macromolecular Crystallography	Structural basis of Smoothened regulation by its extracellular domains Eamon F. X. Byrne , Ria Sircar , Paul S. Miller , George Hedger , Giovanni Luchetti , Sigrid Nachtergaele , Mark D. Tully , Laurel Mydock-mcgrane , Douglas F. Covey , Robert P. Rambo , Mark S. P. Sansom , Simon Newstead , Rajat Rohatgi , Christian Siebold Nature 535, 517 - 522 DOI: 10.1038/nature18934 Diamond Proposal Number(s): [10627] Open Access Show Abstract ▼ Abstract: Developmental signals of the Hedgehog (Hh) and Wnt families are transduced across the membrane by Frizzled-class G-protein-coupled receptors (GPCRs) composed of both a heptahelical transmembrane domain (TMD) and an extracellular cysteine-rich domain (CRD). How the large extracellular domains of GPCRs regulate signalling by the TMD is unknown. We present crystal structures of the Hh signal transducer and oncoprotein Smoothened, a GPCR that contains two distinct ligand-binding sites: one in its TMD and one in the CRD. The CRD is stacked atop the TMD, separated by an intervening wedge-like linker domain. Structure-guided mutations show that the interface between the CRD, linker domain and TMD stabilizes the inactive state of Smoothened. Unexpectedly, we find a cholesterol molecule bound to Smoothened in the CRD binding site. Mutations predicted to prevent cholesterol binding impair the ability of Smoothened to transmit native Hh signals. Binding of a clinically used antagonist, vismodegib, to the TMD induces a conformational change that is propagated to the CRD, resulting in loss of cholesterol from the CRD–linker domain–TMD interface. Our results clarify the structural mechanism by which the activity of a GPCR is controlled by ligand-regulated interactions between its extracellular and transmembrane domains.	Jul 2016

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