7xn9

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of SSTR2 and L-054,522 complex

Structural highlights

7xn9 is a 1 chain structure with sequence from Homo sapiens and Niallia circulans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

XYNA_NIACI SSR2_HUMAN Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Structural insights into ligand recognition and selectivity of somatostatin receptors.,Zhao W, Han S, Qiu N, Feng W, Lu M, Zhang W, Wang M, Zhou Q, Chen S, Xu W, Du J, Chu X, Yi C, Dai A, Hu L, Shen MY, Sun Y, Zhang Q, Ma Y, Zhong W, Yang D, Wang MW, Wu B, Zhao Q Cell Res. 2022 Aug;32(8):761-772. doi: 10.1038/s41422-022-00679-x. Epub 2022 Jun , 23. PMID:35739238^[6]

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

References

↑ Grant M, Collier B, Kumar U. Agonist-dependent dissociation of human somatostatin receptor 2 dimers: a role in receptor trafficking. J Biol Chem. 2004 Aug 27;279(35):36179-83. doi: 10.1074/jbc.M407310200. Epub 2004, Jul 1. PMID:15231824 doi:http://dx.doi.org/10.1074/jbc.M407310200
↑ Grant M, Alturaihi H, Jaquet P, Collier B, Kumar U. Cell growth inhibition and functioning of human somatostatin receptor type 2 are modulated by receptor heterodimerization. Mol Endocrinol. 2008 Oct;22(10):2278-92. doi: 10.1210/me.2007-0334. Epub 2008 Jul, 24. PMID:18653781 doi:http://dx.doi.org/10.1210/me.2007-0334
↑ Le Verche V, Kaindl AM, Verney C, Csaba Z, Peineau S, Olivier P, Adle-Biassette H, Leterrier C, Vitalis T, Renaud J, Dargent B, Gressens P, Dournaud P. The somatostatin 2A receptor is enriched in migrating neurons during rat and human brain development and stimulates migration and axonal outgrowth. PLoS One. 2009;4(5):e5509. doi: 10.1371/journal.pone.0005509. Epub 2009 May 12. PMID:19434240 doi:http://dx.doi.org/10.1371/journal.pone.0005509
↑ Parry JJ, Chen R, Andrews R, Lears KA, Rogers BE. Identification of critical residues involved in ligand binding and G protein signaling in human somatostatin receptor subtype 2. Endocrinology. 2012 Jun;153(6):2747-55. doi: 10.1210/en.2011-1662. Epub 2012 Apr , 11. PMID:22495673 doi:http://dx.doi.org/10.1210/en.2011-1662
↑ Kailey B, van de Bunt M, Cheley S, Johnson PR, MacDonald PE, Gloyn AL, Rorsman P, Braun M. SSTR2 is the functionally dominant somatostatin receptor in human pancreatic beta- and alpha-cells. Am J Physiol Endocrinol Metab. 2012 Nov 1;303(9):E1107-16. doi:, 10.1152/ajpendo.00207.2012. Epub 2012 Aug 28. PMID:22932785 doi:http://dx.doi.org/10.1152/ajpendo.00207.2012
↑ Zhao W, Han S, Qiu N, Feng W, Lu M, Zhang W, Wang M, Zhou Q, Chen S, Xu W, Du J, Chu X, Yi C, Dai A, Hu L, Shen MY, Sun Y, Zhang Q, Ma Y, Zhong W, Yang D, Wang MW, Wu B, Zhao Q. Structural insights into ligand recognition and selectivity of somatostatin receptors. Cell Res. 2022 Aug;32(8):761-772. doi: 10.1038/s41422-022-00679-x. Epub 2022 Jun , 23. PMID:35739238 doi:http://dx.doi.org/10.1038/s41422-022-00679-x

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/7xn9"

@@ Line 3: / Line 3: @@
 <StructureSection load='7xn9' size='340' side='right'caption='[[7xn9]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7xn9]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XN9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XN9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7xn9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Niallia_circulans Niallia circulans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XN9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XN9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GI9:tert-butyl+(2S)-6-azanyl-2-[[(2R,3S)-3-(1H-indol-3-yl)-2-[[4-(2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]carbonylamino]butanoyl]amino]hexanoate'>GI9</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]] 2.6&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Endo-1,4-beta-xylanase Endo-1,4-beta-xylanase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.8 3.2.1.8] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GI9:tert-butyl+(2S)-6-azanyl-2-[[(2R,3S)-3-(1H-indol-3-yl)-2-[[4-(2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]carbonylamino]butanoyl]amino]hexanoate'>GI9</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=7xn9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xn9 OCA], [https://pdbe.org/7xn9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xn9 RCSB], [https://www.ebi.ac.uk/pdbsum/7xn9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xn9 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/SSR2_HUMAN SSR2_HUMAN]] Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.<ref>PMID:15231824</ref> <ref>PMID:18653781</ref> <ref>PMID:19434240</ref> <ref>PMID:22495673</ref> <ref>PMID:22932785</ref>
+[https://www.uniprot.org/uniprot/XYNA_NIACI XYNA_NIACI] [https://www.uniprot.org/uniprot/SSR2_HUMAN SSR2_HUMAN] Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.<ref>PMID:15231824</ref> <ref>PMID:18653781</ref> <ref>PMID:19434240</ref> <ref>PMID:22495673</ref> <ref>PMID:22932785</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Endo-1,4-beta-xylanase]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Feng, W]]
+[[Category: Niallia circulans]]
-[[Category: Han, S]]
+[[Category: Feng W]]
-[[Category: Lu, M]]
+[[Category: Han S]]
-[[Category: Qiu, N]]
+[[Category: Lu M]]
-[[Category: Wang, M W]]
+[[Category: Qiu N]]
-[[Category: Wu, B]]
+[[Category: Wang M-W]]
-[[Category: Yang, D]]
+[[Category: Wu B]]
-[[Category: Zhao, Q]]
+[[Category: Yang D]]
-[[Category: Zhao, W]]
+[[Category: Zhao Q]]
-[[Category: G protein-coupled receptor]]
+[[Category: Zhao W]]
-[[Category: Signaling protein]]
-[[Category: Signaring protein-inhibitor complex]]
-[[Category: Somatostatin receptor 2]]
-[[Category: Structural protein]]

7xn9

From Proteopedia

Current revision

Crystal structure of SSTR2 and L-054,522 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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