9w32: Difference between revisions

Latest revision as of 13:28, 10 February 2026

antagonist 1-bound inactive SSTR5 structure

Structural highlights

9w32 is a 2 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.59Å
Ligands:	A1EVP
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

C562_ECOLX Electron-transport protein of unknown function.SSR5_HUMAN Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition activity of SSTR2 following heterodimerization.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

The somatostatin receptor subtype 5 (SSTR5) is a critical pharmacological target involved in neuroendocrine signaling, metabolic regulation, and tumorigenesis. Despite its therapeutic potential, the structural mechanisms underlying SSTR5 inhibition by nonpeptide antagonists remain largely unresolved. In this study, we present high-resolution cryoelectron microscopy structures of human SSTR5 in complex with two selective small-molecule antagonists, antagonist 1 and S5A1, revealing the receptor's inactive conformation. Both antagonists induce a unique remodeling of extracellular loop 2, which adopts a capping architecture that sterically occludes the orthosteric site, thus preventing agonist access and stabilizing receptor inactivation. Structural analyses and functional experiments elucidate how distinct molecular moieties of the antagonists differentially contribute to inhibitory efficacy, and subtype selectivity. Furthermore, we delineate rational avenues for molecular optimization to enhance therapeutic index and mitigate off-target liabilities. These findings, complementing our previous agonist-bound structures, establish a comprehensive structural foundation for developing improved nonpeptidic SSTR5 antagonists with potential therapeutic applications for type 2 diabetes and related endocrine disorders.

Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5.,Li Y, Xing Z, Hu W, Wu K, Xu HE, Zhao LH Proc Natl Acad Sci U S A. 2025 Dec 23;122(51):e2522515122. doi: , 10.1073/pnas.2522515122. Epub 2025 Dec 19. PMID:41417603^[5]

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

References

↑ Petersenn S, Rasch AC, Böhnke C, Schulte HM. Identification of an upstream pituitary-active promoter of human somatostatin receptor subtype 5. Endocrinology. 2002 Jul;143(7):2626-34. PMID:12072395 doi:10.1210/endo.143.7.8883
↑ Panetta R, Greenwood MT, Warszynska A, Demchyshyn LL, Day R, Niznik HB, Srikant CB, Patel YC. Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28. Mol Pharmacol. 1994 Mar;45(3):417-27 PMID:7908405
↑ O'Carroll AM, Raynor K, Lolait SJ, Reisine T. Characterization of cloned human somatostatin receptor SSTR5. Mol Pharmacol. 1994 Aug;46(2):291-8 PMID:8078491
↑ Yamada Y, Kagimoto S, Kubota A, Yasuda K, Masuda K, Someya Y, Ihara Y, Li Q, Imura H, Seino S, et al.. Cloning, functional expression and pharmacological characterization of a fourth (hSSTR4) and a fifth (hSSTR5) human somatostatin receptor subtype. Biochem Biophys Res Commun. 1993 Sep 15;195(2):844-52. PMID:8373420 doi:10.1006/bbrc.1993.2122
↑ Li Y, Xing Z, Hu W, Wu K, Xu HE, Zhao LH. Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5. Proc Natl Acad Sci U S A. 2025 Dec 23;122(51):e2522515122. PMID:41417603 doi:10.1073/pnas.2522515122

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OCA

[1] Petersenn S, Rasch AC, Böhnke C, Schulte HM. Identification of an upstream pituitary-active promoter of human somatostatin receptor subtype 5. Endocrinology. 2002 Jul;143(7):2626-34. PMID:12072395 doi:10.1210/endo.143.7.8883

[2] Panetta R, Greenwood MT, Warszynska A, Demchyshyn LL, Day R, Niznik HB, Srikant CB, Patel YC. Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28. Mol Pharmacol. 1994 Mar;45(3):417-27 PMID:7908405

[3] O'Carroll AM, Raynor K, Lolait SJ, Reisine T. Characterization of cloned human somatostatin receptor SSTR5. Mol Pharmacol. 1994 Aug;46(2):291-8 PMID:8078491

[4] Yamada Y, Kagimoto S, Kubota A, Yasuda K, Masuda K, Someya Y, Ihara Y, Li Q, Imura H, Seino S, et al.. Cloning, functional expression and pharmacological characterization of a fourth (hSSTR4) and a fifth (hSSTR5) human somatostatin receptor subtype. Biochem Biophys Res Commun. 1993 Sep 15;195(2):844-52. PMID:8373420 doi:10.1006/bbrc.1993.2122

[5] Li Y, Xing Z, Hu W, Wu K, Xu HE, Zhao LH. Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5. Proc Natl Acad Sci U S A. 2025 Dec 23;122(51):e2522515122. PMID:41417603 doi:10.1073/pnas.2522515122

[1]

[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9w32 is ON HOLD  until Paper Publication
+==antagonist 1-bound inactive SSTR5 structure==
+<StructureSection load='9w32' size='340' side='right'caption='[[9w32]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9w32]] 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=9W32 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9W32 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.59&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1EVP:1-[2-[[3,5-diethoxy-4-(4-fluorophenyl)phenyl]methyl]-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl]piperidine-4-carboxylic+acid'>A1EVP</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=9w32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9w32 OCA], [https://pdbe.org/9w32 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9w32 RCSB], [https://www.ebi.ac.uk/pdbsum/9w32 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9w32 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/SSR5_HUMAN SSR5_HUMAN] Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition activity of SSTR2 following heterodimerization.<ref>PMID:12072395</ref> <ref>PMID:7908405</ref> <ref>PMID:8078491</ref> <ref>PMID:8373420</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The somatostatin receptor subtype 5 (SSTR5) is a critical pharmacological target involved in neuroendocrine signaling, metabolic regulation, and tumorigenesis. Despite its therapeutic potential, the structural mechanisms underlying SSTR5 inhibition by nonpeptide antagonists remain largely unresolved. In this study, we present high-resolution cryoelectron microscopy structures of human SSTR5 in complex with two selective small-molecule antagonists, antagonist 1 and S5A1, revealing the receptor's inactive conformation. Both antagonists induce a unique remodeling of extracellular loop 2, which adopts a capping architecture that sterically occludes the orthosteric site, thus preventing agonist access and stabilizing receptor inactivation. Structural analyses and functional experiments elucidate how distinct molecular moieties of the antagonists differentially contribute to inhibitory efficacy, and subtype selectivity. Furthermore, we delineate rational avenues for molecular optimization to enhance therapeutic index and mitigate off-target liabilities. These findings, complementing our previous agonist-bound structures, establish a comprehensive structural foundation for developing improved nonpeptidic SSTR5 antagonists with potential therapeutic applications for type 2 diabetes and related endocrine disorders.
-Authors:
+Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5.,Li Y, Xing Z, Hu W, Wu K, Xu HE, Zhao LH Proc Natl Acad Sci U S A. 2025 Dec 23;122(51):e2522515122. doi: , 10.1073/pnas.2522515122. Epub 2025 Dec 19. PMID:41417603<ref>PMID:41417603</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9w32" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Escherichia coli]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Li Y]]
+[[Category: Xing Z]]
+[[Category: Xu HE]]
+[[Category: Zhao L]]

9w32: Difference between revisions

Latest revision as of 13:28, 10 February 2026

antagonist 1-bound inactive SSTR5 structure

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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