6w25

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with SHU9119

Structural highlights

6w25 is a 2 chain structure with sequence from Homo sapiens, Pyrococcus abyssi GE5 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.75Å
Ligands:	, , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MC4R_HUMAN Obesity due to melanocortin 4 receptor deficiency. The disease is caused by mutations affecting the gene represented in this entry.

Function

Q9V2J8_PYRAB 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).^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003 Mar 20;348(12):1085-95. PMID:12646665 doi:http://dx.doi.org/10.1056/NEJMoa022050
↑ Delhanty PJ, Bouw E, Huisman M, Vervenne RM, Themmen AP, van der Lely AJ, van den Akker EL. Functional characterization of a new human melanocortin-4 receptor homozygous mutation (N72K) that is associated with early-onset obesity. Mol Biol Rep. 2014 Dec;41(12):7967-72. doi: 10.1007/s11033-014-3691-7. Epub 2014 , Aug 28. PMID:25163632 doi:http://dx.doi.org/10.1007/s11033-014-3691-7
↑ 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. Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding. Science. 2020 Apr 24;368(6489):428-433. doi: 10.1126/science.aaz8995. PMID:32327598 doi:http://dx.doi.org/10.1126/science.aaz8995

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6w25"

@@ Line 3: / Line 3: @@
 <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 [http://en.wikipedia.org/wiki/Human Human]. 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 [http://proteopedia.org/fgij/fg.htm?mol=6W25 FirstGlance]. <br>
+<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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene></td></tr>
+</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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><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=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MC4R ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w25 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w25 OCA], [http://pdbe.org/6w25 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w25 RCSB], [http://www.ebi.ac.uk/pdbsum/6w25 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w25 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://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.
+[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 ==
-[[http://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>
+[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 ==
@@ Line 22: / Line 21: @@
 </div>
 <div class="pdbe-citations 6w25" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Alice Clark/BRCT|Alice Clark/BRCT]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Burdsall, K]]
+[[Category: Pyrococcus abyssi GE5]]
-[[Category: Chen, V]]
+[[Category: Synthetic construct]]
-[[Category: Cone, R D]]
+[[Category: Burdsall K]]
-[[Category: Gimenez, L E]]
+[[Category: Chen V]]
-[[Category: Han, G W]]
+[[Category: Cone RD]]
-[[Category: Hernandez, C C]]
+[[Category: Gimenez LE]]
-[[Category: McClary, K]]
+[[Category: Han GW]]
-[[Category: Millhauser, G L]]
+[[Category: Hernandez CC]]
-[[Category: Mittal, S R]]
+[[Category: McClary K]]
-[[Category: Peisley, A]]
+[[Category: Millhauser GL]]
-[[Category: Stauch, B]]
+[[Category: Mittal SR]]
-[[Category: Stevens, R C]]
+[[Category: Peisley A]]
-[[Category: Stevens, S N]]
+[[Category: Stauch B]]
-[[Category: Wein, A H]]
+[[Category: Stevens RC]]
-[[Category: Williams, S Y]]
+[[Category: Stevens SN]]
-[[Category: Wu, L]]
+[[Category: Wein AH]]
-[[Category: Wu, Y]]
+[[Category: Williams SY]]
-[[Category: Yu, J]]
+[[Category: Wu L]]
-[[Category: Zhao, S]]
+[[Category: Wu Y]]
-[[Category: Ca++ cofactor]]
+[[Category: Yu J]]
-[[Category: Gpcr]]
+[[Category: Zhao S]]
-[[Category: Lcp]]
-[[Category: Melanocortin-4 receptor]]
-[[Category: Membrane protein]]
-[[Category: Pgs fusion]]
-[[Category: Shu9119]]

6w25

From Proteopedia

Current revision

Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with SHU9119

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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