View source for 7m94


==Bovine sigma-2 receptor bound to Roluperidone==
<StructureSection load='7m94' size='340' side='right'caption='[[7m94]], [[Resolution|resolution]] 2.71&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7m94]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7M94 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M94 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]] 2.71&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=YT7:Roluperidone'>YT7</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=7m94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m94 OCA], [https://pdbe.org/7m94 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m94 RCSB], [https://www.ebi.ac.uk/pdbsum/7m94 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m94 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SGMR2_BOVIN SGMR2_BOVIN] Intracellular orphan receptor that binds numerous drugs and which is highly expressed in various proliferating cells. Corresponds to the sigma-2 receptor, which is thought to play important role in regulating cell survival, morphology and differentiation. May play a role as a regulator of cellular cholesterol homeostasis. May function as sterol isomerase. May alter the activity of some cytochrome P450 proteins.<ref>PMID:28559337</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The sigma2 receptor has attracted intense interest in cancer imaging(1), psychiatric disease(2), neuropathic pain(3-5) and other areas of biology(6,7). Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone(2) and the tool compound PB28(8). These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 muM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the sigma1 receptor. Crystal structures of two ligands bound to the sigma2 receptor confirmed the docked poses. To investigate the contribution of the sigma2 receptor in pain, two potent sigma2-selective ligands and one potent sigma1/sigma2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model(9), suggesting that the sigma2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.

Structures of the sigma2 receptor enable docking for bioactive ligand discovery.,Alon A, Lyu J, Braz JM, Tummino TA, Craik V, O'Meara MJ, Webb CM, Radchenko DS, Moroz YS, Huang XP, Liu Y, Roth BL, Irwin JJ, Basbaum AI, Shoichet BK, Kruse AC Nature. 2021 Dec 8. pii: 10.1038/s41586-021-04175-x. doi:, 10.1038/s41586-021-04175-x. PMID:34880501<ref>PMID:34880501</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7m94" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Bos taurus]]
[[Category: Large Structures]]
[[Category: Alon A]]
[[Category: Kruse AC]]