View source for 5l7i


==Structure of human Smoothened in complex with Vismodegib==
<StructureSection load='5l7i' size='340' side='right'caption='[[5l7i]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5l7i]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L7I FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MPG:[(Z)-OCTADEC-9-ENYL]+(2R)-2,3-BIS(OXIDANYL)PROPANOATE'>MPG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=VIS:2-CHLORANYL-~{N}-(4-CHLORANYL-3-PYRIDIN-2-YL-PHENYL)-4-METHYLSULFONYL-BENZAMIDE'>VIS</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5l7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l7i OCA], [https://pdbe.org/5l7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l7i RCSB], [https://www.ebi.ac.uk/pdbsum/5l7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l7i ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SMO_HUMAN SMO_HUMAN] G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia.<ref>PMID:19592253</ref> [https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.
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== Publication Abstract from PubMed ==
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.

Structural basis of Smoothened regulation by its extracellular domains.,Byrne EF, Sircar R, Miller PS, Hedger G, Luchetti G, Nachtergaele S, Tully MD, Mydock-McGrane L, Covey DF, Rambo RP, Sansom MS, Newstead S, Rohatgi R Nature. 2016 Jul 28;535(7613):517-22. PMID:27437577<ref>PMID:27437577</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5l7i" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Byrne EXB]]
[[Category: Covey DF]]
[[Category: Hedger G]]
[[Category: Luchetti G]]
[[Category: Miller PS]]
[[Category: Mydock-McGrane L]]
[[Category: Nachtergaele S]]
[[Category: Newstead S]]
[[Category: Rambo RF]]
[[Category: Rohatgi R]]
[[Category: Sansom MSP]]
[[Category: Siebold C]]
[[Category: Sircar R]]
[[Category: Tully MD]]