5L7D

Structure of human Smoothened in complex with cholesterol

5L7D の概要

• エントリーDOI: 10.2210/pdb5l7d/pdb
• 分子名称: Smoothened homolog,Soluble cytochrome b562,Smoothened homolog, 2-acetamido-2-deoxy-beta-D-glucopyranose, CHOLESTEROL, ... (4 entities in total)
• 機能のキーワード: g protein coupled receptor, morphogen signaling, hedgehog signaling, cholesterol, signaling protein, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 142442.99

構造登録者

Byrne, E.F.X.,Sircar, R.,Miller, P.S.,Hedger, G.,Luchetti, G.,Nachtergaele, S.,Tully, M.D.,Mydock-McGrane, L.,Covey, D.F.,Rambo, R.P.,Sansom, M.S.P.,Newstead, S.,Rohatgi, R.,Siebold, C. (登録日: 2016-06-03, 公開日: 2016-07-20, 最終更新日: 2024-11-20)

主引用文献

Byrne, E.F.,Sircar, R.,Miller, P.S.,Hedger, G.,Luchetti, G.,Nachtergaele, S.,Tully, M.D.,Mydock-McGrane, L.,Covey, D.F.,Rambo, R.P.,Sansom, M.S.,Newstead, S.,Rohatgi, R.,Siebold, C.
Structural basis of Smoothened regulation by its extracellular domains.
Nature, 535:517-522, 2016

PubMed Abstract: Developmental signals of the Hedgehog (Hh) and Wnt families are transduced across the membrane by Frizzledclass 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 a top 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.

PubMed: 27437577
DOI: 10.1038/nature18934

実験手法

X-RAY DIFFRACTION (3.2 Å)