View source for 8gy7


==Cryo-EM structure of ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs protein==
<StructureSection load='8gy7' size='340' side='right'caption='[[8gy7]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8gy7]] 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=8GY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GY7 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]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</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=8gy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gy7 OCA], [https://pdbe.org/8gy7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gy7 RCSB], [https://www.ebi.ac.uk/pdbsum/8gy7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gy7 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GNAI3_HUMAN GNAI3_HUMAN] Defects in GNAI3 are the cause of auriculocondylar syndrome 1 (ARCND1) [MIM:[https://omim.org/entry/602483 602483]. ARCND1 is an autosomal dominant craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia.<ref>PMID:22560091</ref> [https://www.uniprot.org/uniprot/GNAS1_HUMAN GNAS1_HUMAN] The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants 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 variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/GNAI3_HUMAN GNAI3_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. G(k) is the stimulatory G protein of receptor-regulated K(+) channels. The active GTP-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> [https://www.uniprot.org/uniprot/GNAS1_HUMAN GNAS1_HUMAN] Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP. GNAS functions downstream of several GPCRs, including beta-adrenergic receptors. XLas isoforms interact with the same set of receptors as GNAS isoforms (By similarity).[UniProtKB:Q6R0H7]
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== Publication Abstract from PubMed ==
G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin receptor 2 (MC2R). Assisted by MRAP1, MC2R responds to adrenocorticotropic hormone (ACTH) and stimulates glucocorticoid biogenesis and cortisol secretion. MC2R activation plays an essential role in the hypothalamic-pituitary-adrenal (HPA) axis that regulates stress response, while its dysfunction causes glucocorticoid insufficiency- or cortisol excess-associated disorders. Here, we present a cryo-electron microscopy (cryo-EM) structure of the ACTH-bound MC2R-G(s)-MRAP1 complex. Our structure, together with mutagenesis analysis, reveals a unique sharp kink at the extracellular region of MRAP1 and the 'seat-belt' effect of MRAP1 on stabilizing ACTH binding and MC2R activation. Mechanisms of ACTH recognition by MC2R and receptor activation are also demonstrated. These findings deepen our understanding of GPCR regulation by accessory proteins and provide valuable insights into the ab initio design of therapeutic agents targeting MC2R.

Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1.,Luo P, Feng W, Ma S, Dai A, Wu K, Chen X, Yuan Q, Cai X, Yang D, Wang MW, Eric Xu H, Jiang Y Cell Res. 2023 Jan;33(1):46-54. doi: 10.1038/s41422-022-00751-6. Epub 2023 Jan 2. PMID:36588120<ref>PMID:36588120</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8gy7" 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 AT]]
[[Category: Feng WB]]
[[Category: Jiang Y]]
[[Category: Luo P]]
[[Category: Ma SS]]
[[Category: Wang MW]]
[[Category: Wu K]]
[[Category: Xu HE]]
[[Category: Yang DH]]
[[Category: Yuan QN]]