4qim: Difference between revisions

Revision as of 15:16, 4 August 2016

Structure of the human smoothened receptor in complex with ANTA XV

Structural highlights

4qim is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	A8T, ZN
Related:	4o9r, 4qin
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1]

Publication Abstract from PubMed

The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8 A resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.

Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs.,Wang C, Wu H, Evron T, Vardy E, Han GW, Huang XP, Hufeisen SJ, Mangano TJ, Urban DJ, Katritch V, Cherezov V, Caron MG, Roth BL, Stevens RC Nat Commun. 2014 Jul 10;5:4355. doi: 10.1038/ncomms5355. PMID:25008467^[2]

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

References

↑ Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, Davis M, Scales SJ, Solloway MJ, de Sauvage FJ, Peterson AS. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol. 2009 Aug 11;19(15):1320-6. doi: 10.1016/j.cub.2009.06.046. Epub 2009, Jul 9. PMID:19592253 doi:https://dx.doi.org/10.1016/j.cub.2009.06.046
↑ Wang C, Wu H, Evron T, Vardy E, Han GW, Huang XP, Hufeisen SJ, Mangano TJ, Urban DJ, Katritch V, Cherezov V, Caron MG, Roth BL, Stevens RC. Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun. 2014 Jul 10;5:4355. doi: 10.1038/ncomms5355. PMID:25008467 doi:https://dx.doi.org/10.1038/ncomms5355

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, Davis M, Scales SJ, Solloway MJ, de Sauvage FJ, Peterson AS. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol. 2009 Aug 11;19(15):1320-6. doi: 10.1016/j.cub.2009.06.046. Epub 2009, Jul 9. PMID:19592253 doi:https://dx.doi.org/10.1016/j.cub.2009.06.046

[2] Wang C, Wu H, Evron T, Vardy E, Han GW, Huang XP, Hufeisen SJ, Mangano TJ, Urban DJ, Katritch V, Cherezov V, Caron MG, Roth BL, Stevens RC. Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun. 2014 Jul 10;5:4355. doi: 10.1038/ncomms5355. PMID:25008467 doi:https://dx.doi.org/10.1038/ncomms5355

[1]

[2]

@@ Line 1: / Line 1: @@
 ==Structure of the human smoothened receptor in complex with ANTA XV==
 <StructureSection load='4qim' size='340' side='right' caption='[[4qim]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A8T:2-{6-[4-(4-BENZYLPHTHALAZIN-1-YL)PIPERAZIN-1-YL]PYRIDIN-3-YL}PROPAN-2-OL'>A8T</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4o9r|4o9r]], [[4qin|4qin]]</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=4qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qim OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qim RCSB], [http://www.ebi.ac.uk/pdbsum/4qim PDBsum]</span></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=4qim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qim OCA], [http://pdbe.org/4qim PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qim RCSB], [http://www.ebi.ac.uk/pdbsum/4qim PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qim ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4qim" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4qim: Difference between revisions

Revision as of 15:16, 4 August 2016

Structure of the human smoothened receptor in complex with ANTA XV

Structural highlights

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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