GPCRs through the keyhole: the role of protein flexibility in ligand binding to β-adrenoceptors

G protein-coupled receptors (GPCRs) are proteins of pharmaceutical importance, with over 30% of all drugs in clinical use targeting them. Increasing numbers of X-ray crystal (XRC) structures of GPCRs offer a wealth of data relating to ligand binding. For the β-adrenoceptors (β-ARs), XRC structures are available for human β2- and turkey β1-subtypes, in complexes with a range of ligands. While these structures provide insight into the origins of ligand structure-activity relationships (SARs), questions remain. The ligands in all published complexed XRC structures lack extensive substitution, with no obvious way the ligand-binding site can accommodate β1-AR-selective antagonists with extended side-chains para- to the common aryloxypropanolamine pharmacophore. Using standard computational docking tools with such ligands generally returns poses that fail to explain known SARs. Application of our Active Site Pressurisation modelling method to β-AR XRC structures and homology models, however, reveals a dynamic area in the ligand-binding pocket that, through minor changes in amino acid side chain orientations, opens a fissure between transmembrane helices H4 and H5, exposing intra-membrane space. This fissure, which we term the “keyhole”, is ideally located to accommodate extended moieties present in many high-affinity β1-AR-selective ligands, allowing the rest of the ligand structure to adopt a canonical pose in the orthosteric binding site. We propose the keyhole may be a feature of both β1- and β2-ARs, but that subtle structural differences exist between the two, contributing to subtype-selectivity. This has consequences for the rational design of future generations of subtype-selective ligands for these therapeutically important targets

First-Year Papers Cover Page and Editorial Board

Volume 17, 2012 – 2013 EDITORS First-Year Program Margaret Lindsey, Dean Erin Valentino, Research Education Librarian Dania Field, Program Assistant First-Year Mentors Andrew Bannon-Guasp ‘13 Elizabeth Preysner ‘13 Megan Baxter ‘13 Junius Ross-Martin ‘15 Emma Belloumo ‘13 Lillian Young ‘13 Elizabeth Bilfinger ’13 Abigail Whalen ‘15 Editing, Layout, and Publishing Dania Field Amy Harrell Elizabeth Preysner The First-Year Papers were established in 1996-1997 to recognize the excellent written work of the first-year students at Trinity College. Each year, submissions are drawn from First-Year Seminars and from courses associated with the Cities, Guided Studies, InterArts, and Interdisciplinary Science Programs. The First-Year Papers Volume 17, 2012 – 2013 Published by Trinity College Hartford, Connecticut, September 201

First-Year Papers Cover Art and Editorial Board

Volume 16, 2011 – 2012 EDITORS First-Year Program Margaret Lindsey, Dean Erin Valentino, Research Education Librarian Dania Field, Program Assistant First-Year Mentors Perin Adams ‘13 Logan Marro ‘13 Jenna Allen ‘12 Caroline Peck ‘12 Katie Joachim ‘12 Liz Sherman ‘13 Shaun Stuer ‘13 Editing, Layout, and Publishing Dania Field Amy Harrell Elizabeth Preysner The First-Year Papers were established in 1996-1997 to recognize the excellent written work of the first-year students at Trinity College. Each year, submissions are drawn from First-Year Seminars and from courses associated with the Cities, Guided Studies, InterArts, and Interdisciplinary Science Programs. The First-Year Papers Volume 16, 2011 – 2012 Published by Trinity College Hartford, Connecticut, September 201