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==Cryo-EM structure of Urocortin 1-bound Corticotropin-releasing factor 2 receptor in complex with Gs protein and Nb35==
==Cryo-EM structure of Urocortin 1-bound Corticotropin-releasing factor 2 receptor in complex with Gs protein and Nb35==
<StructureSection load='6pb1' size='340' side='right'caption='[[6pb1]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
<SX load='6pb1' size='340' side='right' viewer='molstar' caption='[[6pb1]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6pb1]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PB1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PB1 FirstGlance]. <br>
<table><tr><td colspan='2'>[[6pb1]] is a 6 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=6PB1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PB1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6pb0|6pb0]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6pb1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pb1 OCA], [http://pdbe.org/6pb1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pb1 RCSB], [http://www.ebi.ac.uk/pdbsum/6pb1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pb1 ProSAT]</span></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=6pb1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pb1 OCA], [https://pdbe.org/6pb1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pb1 RCSB], [https://www.ebi.ac.uk/pdbsum/6pb1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pb1 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://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 ==
[[http://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>  [[http://www.uniprot.org/uniprot/UCN1_HUMAN UCN1_HUMAN]] Acts in vitro to stimulate the secretion of adrenocorticotropic hormone (ACTH). Binds with high affinity to CRF receptor types 1, 2-alpha, and 2-beta. [[http://www.uniprot.org/uniprot/CRFR2_HUMAN CRFR2_HUMAN]] G-protein coupled receptor for CRH (corticotropin-releasing factor), UCN (urocortin), UCN2 and UCN3. Has high affinity for UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. [[http://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref>  [[http://www.uniprot.org/uniprot/GBG2_HUMAN GBG2_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity).
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs.
Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs.


Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors.,Ma S, Shen Q, Zhao LH, Mao C, Zhou XE, Shen DD, de Waal PW, Bi P, Li C, Jiang Y, Wang MW, Sexton PM, Wootten D, Melcher K, Zhang Y, Xu HE Mol Cell. 2020 Feb 6;77(3):669-680.e4. doi: 10.1016/j.molcel.2020.01.013. Epub, 2020 Jan 30. PMID:32004470<ref>PMID:32004470</ref>
, PMID:32004470<ref>PMID:32004470</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 6pb1" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 6pb1" style="background-color:#fffaf0;"></div>
==See Also==
*[[GTP-binding protein 3D structures|GTP-binding protein 3D structures]]
*[[Transducin 3D structures|Transducin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</SX>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bi, P]]
[[Category: Synthetic construct]]
[[Category: Jiang, Y]]
[[Category: Bi P]]
[[Category: Li, C]]
[[Category: Jiang Y]]
[[Category: Ma, S]]
[[Category: Li C]]
[[Category: Mao, C]]
[[Category: Ma S]]
[[Category: Melcher, K]]
[[Category: Mao C]]
[[Category: Sexton, P M]]
[[Category: Melcher K]]
[[Category: Shen, D D]]
[[Category: Sexton PM]]
[[Category: Shen, Q]]
[[Category: Shen D-D]]
[[Category: Waal, P W.de]]
[[Category: Shen Q]]
[[Category: Wang, M W]]
[[Category: Wang M-W]]
[[Category: Wootten, D]]
[[Category: Wootten D]]
[[Category: Xu, H E]]
[[Category: Xu HE]]
[[Category: Zhang, Y]]
[[Category: Zhang Y]]
[[Category: Zhao, L H]]
[[Category: Zhao L-H]]
[[Category: Zhou, X E]]
[[Category: Zhou XE]]
[[Category: Corticotropin-releasing factor 2 receptor]]
[[Category: De Waal PW]]
[[Category: Gpcr]]
[[Category: Gs protein]]
[[Category: Signaling protein]]
[[Category: Urocortins1]]
Retrieved from "https://proteopedia.org/6pb1"