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7f83

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Crystal Structure of a receptor in Complex with inverse agonist

Structural highlights

7f83 is a 2 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.94Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GHSR_HUMAN Short stature due to GHSR deficiency. The disease is caused by variants affecting the gene represented in this entry.

Function

C562_ECOLX Electron-transport protein of unknown function.GHSR_HUMAN Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine).^[1] ^[2]

Publication Abstract from PubMed

Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.

Molecular mechanism of agonism and inverse agonism in ghrelin receptor.,Qin J, Cai Y, Xu Z, Ming Q, Ji SY, Wu C, Zhang H, Mao C, Shen DD, Hirata K, Ma Y, Yan W, Zhang Y, Shao Z Nat Commun. 2022 Jan 13;13(1):300. doi: 10.1038/s41467-022-27975-9. PMID:35027551^[3]

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

References

↑ Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999 Dec 9;402(6762):656-60. PMID:10604470 doi:http://dx.doi.org/10.1038/45230
↑ Smith RG, Leonard R, Bailey AR, Palyha O, Feighner S, Tan C, Mckee KK, Pong SS, Griffin P, Howard A. Growth hormone secretagogue receptor family members and ligands. Endocrine. 2001 Feb;14(1):9-14. PMID:11322507 doi:http://dx.doi.org/ENDO:14:1:009
↑ Qin J, Cai Y, Xu Z, Ming Q, Ji SY, Wu C, Zhang H, Mao C, Shen DD, Hirata K, Ma Y, Yan W, Zhang Y, Shao Z. Molecular mechanism of agonism and inverse agonism in ghrelin receptor. Nat Commun. 2022 Jan 13;13(1):300. doi: 10.1038/s41467-022-27975-9. PMID:35027551 doi:http://dx.doi.org/10.1038/s41467-022-27975-9

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7f83"

Categories: Escherichia coli | Homo sapiens | Large Structures | Shao Z | Xu Z

@@ Line 3: / Line 3: @@
 <StructureSection load='7f83' size='340' side='right'caption='[[7f83]], [[Resolution|resolution]] 2.94&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7f83]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F83 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F83 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7f83]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F83 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F83 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1KQ:2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone'>1KQ</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</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]] 2.94&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1KQ:2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone'>1KQ</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</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=7f83 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f83 OCA], [https://pdbe.org/7f83 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f83 RCSB], [https://www.ebi.ac.uk/pdbsum/7f83 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f83 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/GHSR_HUMAN GHSR_HUMAN]] Short stature due to GHSR deficiency. The disease is caused by variants affecting the gene represented in this entry.
+[https://www.uniprot.org/uniprot/GHSR_HUMAN GHSR_HUMAN] Short stature due to GHSR deficiency. The disease is caused by variants affecting the gene represented in this entry.
 == Function ==
-[[https://www.uniprot.org/uniprot/GHSR_HUMAN GHSR_HUMAN]] Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine).<ref>PMID:10604470</ref> <ref>PMID:11322507</ref>
+[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/GHSR_HUMAN GHSR_HUMAN] Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine).<ref>PMID:10604470</ref> <ref>PMID:11322507</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Escherichia coli]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Shao, Z]]
+[[Category: Shao Z]]
-[[Category: Xu, Z]]
+[[Category: Xu Z]]
-[[Category: Ghrelin]]
-[[Category: Gpcr]]
-[[Category: Inverse agonist]]
-[[Category: Signaling protein]]

7f83

From Proteopedia

Current revision

Crystal Structure of a receptor in Complex with inverse agonist

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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