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Coupling of receptor conformation and ligand orientation determine graded activity.

<div class='caption-title'>An Energy Landscape Model of Ligand Binding</div>
<div class='caption-title'>(a) Estrogen responsive luciferase assays were performed by transfection of a 3xERE-luc reporter in ER-positive MCF-7 cells. After 24 hr, cells were treated with the indicated doses of ligands overnight, and then assessed for luciferase activity.</div>
<div class='caption-title'>(a) A 2Fo-Fc map shows the electron density for the ligand, and is contoured to 2.0 σ.</div>
Bruning JB, Parent AA, Gil G, Zhao M, Nowak J, Pace MC, Smith CL, Afonine PV, Adams PD, Katzenellenbogen JA, Nettles KW
OpenAccess logo Nat Chem Biol 6 837-43 (2010)
Related entries: 2qxs, 3os8, 3os9, 3osa

Cited: 79 times
EuropePMC logo PMID: 20924370

Abstract

Small molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of-allostery' mutations that mimic the effects of ligand in driving protein conformation allowed crystallization of the partial agonist ligand WAY-169916 with both the canonical active and inactive conformations of the estrogen receptor. The intermediate transcriptional activity induced by WAY-169916 is associated with the ligand binding differently to the active and inactive conformations of the receptor. Analyses of a series of chemical derivatives demonstrated that altering the ensemble of ligand binding orientations changes signaling output. The coupling of different ligand binding orientations to distinct active and inactive protein conformations defines a new mechanism for titrating allosteric signaling activity.

Reviews - 2qzo mentioned but not cited (1)

  1. Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands. Ng HW, Perkins R, Tong W, Hong H. Int J Environ Res Public Health 11 8709-8742 (2014)

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