View source for 7bph


==Crystal structure of GppNHp-bound GNAS in complex with the cyclic peptide inhibitor GN13==
<StructureSection load='7bph' size='340' side='right'caption='[[7bph]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7bph]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] 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=7BPH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BPH 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]] 1.57&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DTY:D-TYROSINE'>DTY</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=7bph FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bph OCA], [https://pdbe.org/7bph PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bph RCSB], [https://www.ebi.ac.uk/pdbsum/7bph PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bph ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GNAS2_HUMAN GNAS2_HUMAN] Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/GNAS2_HUMAN GNAS2_HUMAN] Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).<ref>PMID:12391161</ref> <ref>PMID:17110384</ref> <ref>PMID:21488135</ref> <ref>PMID:26206488</ref> <ref>PMID:8702665</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, with the exception of the Galpha subunit, Galphas. GTPases remain largely undruggable given the difficulty of displacing high-affinity guanine nucleotides and the lack of other drug binding sites. We explored a chemical library of 10(12) cyclic peptides to expand the chemical search for inhibitors of this enzyme class. We identified two macrocyclic peptides, GN13 and GD20, that antagonize the active and inactive states of Galphas, respectively. Both macrocyclic peptides fine-tune Galphas activity with high nucleotide-binding-state selectivity and G protein class-specificity. Co-crystal structures reveal that GN13 and GD20 distinguish the conformational differences within the switch II/alpha3 pocket. Cell-permeable analogs of GN13 and GD20 modulate Galphas/Gbetagamma signaling in cells through binding to crystallographically defined pockets. The discovery of cyclic peptide inhibitors targeting Galphas provides a path for further development of state-dependent GTPase inhibitors.

State-selective modulation of heterotrimeric Galphas signaling with macrocyclic peptides.,Dai SA, Hu Q, Gao R, Blythe EE, Touhara KK, Peacock H, Zhang Z, von Zastrow M, Suga H, Shokat KM Cell. 2022 Oct 13;185(21):3950-3965.e25. doi: 10.1016/j.cell.2022.09.019. Epub, 2022 Sep 27. PMID:36170854<ref>PMID:36170854</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7bph" style="background-color:#fffaf0;"></div>

==See Also==
*[[Transducin 3D structures|Transducin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Dai S]]
[[Category: Hu Q]]
[[Category: Shokat KM]]