View source for 6w25


==Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with SHU9119==
<StructureSection load='6w25' size='340' side='right'caption='[[6w25]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6w25]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Pyrococcus_abyssi_GE5 Pyrococcus abyssi GE5] 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=6W25 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W25 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]] 2.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4J2:(2R)-2-AMINO-3-(NAPHTHALEN-2-YL)PROPANOIC+ACID'>4J2</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</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=6w25 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w25 OCA], [https://pdbe.org/6w25 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w25 RCSB], [https://www.ebi.ac.uk/pdbsum/6w25 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w25 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MC4R_HUMAN MC4R_HUMAN] Obesity due to melanocortin 4 receptor deficiency. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/Q9V2J8_PYRAB Q9V2J8_PYRAB] [https://www.uniprot.org/uniprot/MC4R_HUMAN MC4R_HUMAN] Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP).<ref>PMID:12646665</ref> <ref>PMID:25163632</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca(2+) is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca(2+) increases the affinity and potency of the endogenous agonist alpha-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.

Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding.,Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH, Han GW, McClary K, Mittal SR, Burdsall K, Stauch B, Wu L, Stevens SN, Peisley A, Williams SY, Chen V, Millhauser GL, Zhao S, Cone RD, Stevens RC Science. 2020 Apr 24;368(6489):428-433. doi: 10.1126/science.aaz8995. PMID:32327598<ref>PMID:32327598</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6w25" style="background-color:#fffaf0;"></div>

==See Also==
*[[Alice Clark/BRCT|Alice Clark/BRCT]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Pyrococcus abyssi GE5]]
[[Category: Synthetic construct]]
[[Category: Burdsall K]]
[[Category: Chen V]]
[[Category: Cone RD]]
[[Category: Gimenez LE]]
[[Category: Han GW]]
[[Category: Hernandez CC]]
[[Category: McClary K]]
[[Category: Millhauser GL]]
[[Category: Mittal SR]]
[[Category: Peisley A]]
[[Category: Stauch B]]
[[Category: Stevens RC]]
[[Category: Stevens SN]]
[[Category: Wein AH]]
[[Category: Williams SY]]
[[Category: Wu L]]
[[Category: Wu Y]]
[[Category: Yu J]]
[[Category: Zhao S]]