View source for 8zcj


==Cryo-EM structure of the pasireotide-bound SSTR5-Gi complex==
<StructureSection load='8zcj' size='340' side='right'caption='[[8zcj]], [[Resolution|resolution]] 3.09&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8zcj]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Oplophorus_gracilirostris Oplophorus gracilirostris], [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ZCJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ZCJ 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]] 3.09&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=004:(2S)-AMINO(PHENYL)ETHANOIC+ACID'>004</scene>, <scene name='pdbligand=DTR:D-TRYPTOPHAN'>DTR</scene>, <scene name='pdbligand=HYP:4-HYDROXYPROLINE'>HYP</scene>, <scene name='pdbligand=PHA:PHENYLALANINAL'>PHA</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=8zcj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8zcj OCA], [https://pdbe.org/8zcj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8zcj RCSB], [https://www.ebi.ac.uk/pdbsum/8zcj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8zcj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GNAI1_HUMAN GNAI1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.<ref>PMID:17635935</ref> <ref>PMID:17264214</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 A and 3.24 A, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/(D)Trp of pasireotide and SSTR5. Moreover, we find that the Q(2.63), N(6.55), F(7.35) and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.

Structural insights into somatostatin receptor 5 bound with cyclic peptides.,Li YG, Meng XY, Yang X, Ling SL, Shi P, Tian CL, Yang F Acta Pharmacol Sin. 2024 Jun 26. doi: 10.1038/s41401-024-01314-8. PMID:38926478<ref>PMID:38926478</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8zcj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Oplophorus gracilirostris]]
[[Category: Rattus norvegicus]]
[[Category: Synthetic construct]]
[[Category: Li YG]]
[[Category: Ling SL]]
[[Category: Meng XY]]
[[Category: Shi P]]
[[Category: Tian CL]]
[[Category: Yang F]]
[[Category: Yang XR]]