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6o3c

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Crystal structure of active Smoothened bound to SAG21k, cholesterol, and NbSmo8

Structural highlights

6o3c is a 2 chain structure with sequence from Lama glama and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SMO_MOUSE 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) (By similarity). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (PubMed:25644602).[UniProtKB:Q99835]^[1]

Publication Abstract from PubMed

Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration(1). Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma(2). Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models(3-5), a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembrane pocket. We propose that the inactivation of PTCH1 by Hedgehog allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. These results-combined with signalling studies and molecular dynamics simulations-delineate the structural basis for PTCH1-SMO regulation, and suggest a strategy for overcoming clinical resistance to SMO inhibitors.

Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.,Deshpande I, Liang J, Hedeen D, Roberts KJ, Zhang Y, Ha B, Latorraca NR, Faust B, Dror RO, Beachy PA, Myers BR, Manglik A Nature. 2019 Jul;571(7764):284-288. doi: 10.1038/s41586-019-1355-4. Epub 2019 Jul, 1. PMID:31263273^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chong YC, Mann RK, Zhao C, Kato M, Beachy PA. Bifurcating action of Smoothened in Hedgehog signaling is mediated by Dlg5. Genes Dev. 2015 Feb 1;29(3):262-76. doi: 10.1101/gad.252676.114. PMID:25644602 doi:http://dx.doi.org/10.1101/gad.252676.114
↑ Deshpande I, Liang J, Hedeen D, Roberts KJ, Zhang Y, Ha B, Latorraca NR, Faust B, Dror RO, Beachy PA, Myers BR, Manglik A. Smoothened stimulation by membrane sterols drives Hedgehog pathway activity. Nature. 2019 Jul;571(7764):284-288. doi: 10.1038/s41586-019-1355-4. Epub 2019 Jul, 1. PMID:31263273 doi:http://dx.doi.org/10.1038/s41586-019-1355-4

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6o3c"

@@ Line 3: / Line 3: @@
 <StructureSection load='6o3c' size='340' side='right'caption='[[6o3c]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6o3c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O3C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O3C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6o3c]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Lama_glama Lama glama] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O3C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O3C FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=LKD:3-chloro-4,7-difluoro-N-{[2-methoxy-5-(pyridin-4-yl)phenyl]methyl}-N-[trans-4-(methylamino)cyclohexyl]-1-benzothiophene-2-carboxamide'>LKD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OLB:(2S)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLB</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Smo, Smoh ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=LKD:3-chloro-4,7-difluoro-N-{[2-methoxy-5-(pyridin-4-yl)phenyl]methyl}-N-[trans-4-(methylamino)cyclohexyl]-1-benzothiophene-2-carboxamide'>LKD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OLB:(2S)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLB</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6o3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3c OCA], [http://pdbe.org/6o3c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o3c RCSB], [http://www.ebi.ac.uk/pdbsum/6o3c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3c ProSAT]</span></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=6o3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3c OCA], [https://pdbe.org/6o3c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o3c RCSB], [https://www.ebi.ac.uk/pdbsum/6o3c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3c ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/SMO_MOUSE SMO_MOUSE]] 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) (By similarity). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (PubMed:25644602).[UniProtKB:Q99835]<ref>PMID:25644602</ref>
+[https://www.uniprot.org/uniprot/SMO_MOUSE SMO_MOUSE] 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) (By similarity). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (PubMed:25644602).[UniProtKB:Q99835]<ref>PMID:25644602</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Lama glama]]
 [[Category: Large Structures]]
-[[Category: Lk3 transgenic mice]]
+[[Category: Mus musculus]]
-[[Category: Beachy, P A]]
+[[Category: Beachy PA]]
-[[Category: Deshpande, I S]]
+[[Category: Deshpande IS]]
-[[Category: Dror, R O]]
+[[Category: Dror RO]]
-[[Category: Faust, B]]
+[[Category: Faust B]]
-[[Category: Ha, B]]
+[[Category: Ha B]]
-[[Category: Hedeen, D]]
+[[Category: Hedeen D]]
-[[Category: Latorraca, N R]]
+[[Category: Latorraca NR]]
-[[Category: Liang, J]]
+[[Category: Liang J]]
-[[Category: Manglik, A]]
+[[Category: Manglik A]]
-[[Category: Myers, B R]]
+[[Category: Myers BR]]
-[[Category: Roberts, K J]]
+[[Category: Roberts KJ]]
-[[Category: Zhang, Y]]
+[[Category: Zhang Y]]
-[[Category: Cholesterol]]
-[[Category: Gpcr]]
-[[Category: Hedgehog]]
-[[Category: Sag]]
-[[Category: Signaling]]
-[[Category: Signaling protein]]
-[[Category: Smoothened]]

6o3c

From Proteopedia

Current revision

Crystal structure of active Smoothened bound to SAG21k, cholesterol, and NbSmo8

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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