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Three-Dimensional Structure of the Smoothened Receptor: Implications for Drug Discovery

  • Didier RognanEmail author
  • Isabelle Mus-Veteau
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 16)

Abstract

The recently described high resolution three-dimensional structures of the transmembrane and the extracellular domains of the human Smoothened (Smo) receptor higlight both conserved and unique structural features of this G protein-coupled receptor. It enables a better understanding of very subtle molecular mechanisms regulating Smo function and demonstrates the very plastic nature of this receptor which is able to accommodate a diverse array of small molecular weight ligands through several binding sites. This structural information should pave the way for designing small molecular weight modulators of Smo function targeting different binding sites and insensitive to clinically observed receptor mutations.

Keywords

Binding mode Cystein-rich domain Drug design Transmembrane domain X-ray structure 

Abbreviations

BCC

Basal cell carcinoma

Bud

Budesonide

drSmo

Drosophila Smoothened

ECD

Extracellular domain

ECD

Cystein-rich domain

ECL

Extracellular loop

GPCR

G protein-coupled receptor

hSmo

Human Smoothened

Hh

Hedgehog

ICL

Intracellular loop

NMR

Nuclear magnetic resonance

Smo

Smoothened

TM

Transmembrane

zSmo

Zebrafish Smoothened

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Laboratoire d’Innovation ThérapeutiqueUMR 7200 CNRS-Université de StrasbourgIllkirchFrance
  2. 2.Institut de Pharmacologie Moléculaire et CellulaireUMR 7275 CNRS-Université de Nice-Sophia AntipolisIllkirchFrance

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