6uun
From Proteopedia
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<StructureSection load='6uun' size='340' side='right'caption='[[6uun]], [[Resolution|resolution]] 3.00Å' scene=''> | <StructureSection load='6uun' size='340' side='right'caption='[[6uun]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6uun]] is a 7 chain structure with sequence from [ | + | <table><tr><td colspan='2'>[[6uun]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UUN FirstGlance]. <br> |
| - | </td></tr><tr id=' | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3Å</td></tr> |
| - | <tr id=' | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6uun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uun OCA], [https://pdbe.org/6uun PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uun RCSB], [https://www.ebi.ac.uk/pdbsum/6uun PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uun 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/ADML_HUMAN ADML_HUMAN]] AM and PAMP are potent hypotensive and vasodilatator agents. Numerous actions have been reported most related to the physiologic control of fluid and electrolyte homeostasis. In the kidney, am is diuretic and natriuretic, and both am and pamp inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptides at physiologically relevant doses inhibit basal ACTH secretion. Both peptides appear to act in brain and pituitary gland to facilitate the loss of plasma volume, actions which complement their hypotensive effects in blood vessels. [[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). [[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/RAMP2_HUMAN RAMP2_HUMAN]] Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.<ref>PMID:22102369</ref> <ref>PMID:9620797</ref> [[http://www.uniprot.org/uniprot/CALRL_HUMAN CALRL_HUMAN]] Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.<ref>PMID:22102369</ref> [[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> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) receptors are critically important for metabolism, vascular tone, and inflammatory response. AM receptors are also required for normal lymphatic and blood vascular development and angiogenesis. They play a pivotal role in embryo implantation and fertility and can provide protection against hypoxic and oxidative stress. CGRP and AM receptors are heterodimers of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) (CGRPR), as well as RAMP2 or RAMP3 (AM1R and AM2R, respectively). However, the mechanistic basis for RAMP modulation of CLR phenotype is unclear. In this study, we report the cryo-EM structure of the AM1R in complex with AM and Gs at a global resolution of 3.0 A, and structures of the AM2R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 A, respectively. The structures reveal distinctions in the primary orientation of the extracellular domains (ECDs) relative to the receptor core and distinct positioning of extracellular loop 3 (ECL3) that are receptor-dependent. Analysis of dynamic data present in the cryo-EM micrographs revealed additional distinctions in the extent of mobility of the ECDs. Chimeric exchange of the linker region of the RAMPs connecting the TM helix and the ECD supports a role for this segment in controlling receptor phenotype. Moreover, a subset of the motions of the ECD appeared coordinated with motions of the G protein relative to the receptor core, suggesting that receptor ECD dynamics could influence G protein interactions. This work provides fundamental advances in our understanding of GPCR function and how this can be allosterically modulated by accessory proteins. | Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) receptors are critically important for metabolism, vascular tone, and inflammatory response. AM receptors are also required for normal lymphatic and blood vascular development and angiogenesis. They play a pivotal role in embryo implantation and fertility and can provide protection against hypoxic and oxidative stress. CGRP and AM receptors are heterodimers of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) (CGRPR), as well as RAMP2 or RAMP3 (AM1R and AM2R, respectively). However, the mechanistic basis for RAMP modulation of CLR phenotype is unclear. In this study, we report the cryo-EM structure of the AM1R in complex with AM and Gs at a global resolution of 3.0 A, and structures of the AM2R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 A, respectively. The structures reveal distinctions in the primary orientation of the extracellular domains (ECDs) relative to the receptor core and distinct positioning of extracellular loop 3 (ECL3) that are receptor-dependent. Analysis of dynamic data present in the cryo-EM micrographs revealed additional distinctions in the extent of mobility of the ECDs. Chimeric exchange of the linker region of the RAMPs connecting the TM helix and the ECD supports a role for this segment in controlling receptor phenotype. Moreover, a subset of the motions of the ECD appeared coordinated with motions of the G protein relative to the receptor core, suggesting that receptor ECD dynamics could influence G protein interactions. This work provides fundamental advances in our understanding of GPCR function and how this can be allosterically modulated by accessory proteins. | ||
| - | + | , PMID:32296767<ref>PMID:32296767</ref> | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 6uun" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6uun" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Transducin 3D structures|Transducin 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Lama glama]] |
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Belousoff | + | [[Category: Belousoff MJ]] |
| - | [[Category: Danev | + | [[Category: Danev R]] |
| - | [[Category: Liang | + | [[Category: Liang YL]] |
| - | [[Category: Sexton | + | [[Category: Sexton P]] |
| - | + | ||
| - | + | ||
| - | + | ||
Current revision
CryoEM Structure of the active Adrenomedullin 1 receptor G protein complex with adrenomedullin peptide
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