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Yorodumi- EMDB-20906: CryoEM Structure of the active Adrenomedullin 2 receptor G protei... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-20906 | ||||||||||||||||||
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Title | CryoEM Structure of the active Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide | ||||||||||||||||||
Map data | Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide | ||||||||||||||||||
Sample |
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Function / homology | Function and homology information G protein-coupled receptor signaling pathway involved in heart process / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin binding / cellular response to sucrose stimulus / cross-receptor inhibition within G protein-coupled receptor heterodimer / amylin receptor complex 3 / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway ...G protein-coupled receptor signaling pathway involved in heart process / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin binding / cellular response to sucrose stimulus / cross-receptor inhibition within G protein-coupled receptor heterodimer / amylin receptor complex 3 / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity / calcitonin receptor activity / vascular associated smooth muscle cell proliferation / calcitonin gene-related peptide receptor activity / amylin receptor signaling pathway / Calcitonin-like ligand receptors / regulation of systemic arterial blood pressure / feeding behavior / digestion / positive regulation of heart rate / positive regulation of receptor recycling / positive regulation of protein kinase A signaling / response to amyloid-beta / PKA activation in glucagon signalling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / Hedgehog 'off' state / coreceptor activity / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cellular response to hormone stimulus / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to estradiol stimulus / adenylate cyclase activator activity / negative regulation of blood pressure / positive regulation of calcium-mediated signaling / positive regulation of protein localization to plasma membrane / trans-Golgi network membrane / protein localization to plasma membrane / G protein-coupled receptor activity / intracellular protein transport / G-protein beta/gamma-subunit complex binding / bone development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / hormone activity / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / receptor internalization / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / platelet aggregation / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / positive regulation of angiogenesis / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / calcium ion transport / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / protein transport / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / heart development / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / amyloid-beta binding Similarity search - Function | ||||||||||||||||||
Biological species | Homo sapiens (human) / Lama glama (llama) | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.3 Å | ||||||||||||||||||
Authors | Belousoff MJ / Liang YL / Sexton P / Danev R | ||||||||||||||||||
Funding support | Australia, Japan, 5 items
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Citation | Journal: ACS Pharmacol Transl Sci / Year: 2020 Title: Structure and Dynamics of Adrenomedullin Receptors AM and AM Reveal Key Mechanisms in the Control of Receptor Phenotype by Receptor Activity-Modifying Proteins. Authors: Yi-Lynn Liang / Matthew J Belousoff / Madeleine M Fletcher / Xin Zhang / Maryam Khoshouei / Giuseppe Deganutti / Cassandra Koole / Sebastian G B Furness / Laurence J Miller / Debbie L Hay / ...Authors: Yi-Lynn Liang / Matthew J Belousoff / Madeleine M Fletcher / Xin Zhang / Maryam Khoshouei / Giuseppe Deganutti / Cassandra Koole / Sebastian G B Furness / Laurence J Miller / Debbie L Hay / Arthur Christopoulos / Christopher A Reynolds / Radostin Danev / Denise Wootten / Patrick M Sexton / Abstract: 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 ...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 (AMR and AMR, respectively). However, the mechanistic basis for RAMP modulation of CLR phenotype is unclear. In this study, we report the cryo-EM structure of the AMR in complex with AM and Gs at a global resolution of 3.0 Å, and structures of the AMR in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 Å, 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. | ||||||||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_20906.map.gz | 7.7 MB | EMDB map data format | |
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Header (meta data) | emd-20906-v30.xml emd-20906.xml | 31.5 KB 31.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_20906_fsc.xml | 10.2 KB | Display | FSC data file |
Images | emd_20906.png | 47.3 KB | ||
Masks | emd_20906_msk_1.map | 91.1 MB | Mask map | |
Others | emd_20906_additional_1.map.gz emd_20906_additional_2.map.gz emd_20906_additional_3.map.gz emd_20906_half_map_1.map.gz emd_20906_half_map_2.map.gz | 59.2 MB 71.5 MB 2 MB 71.8 MB 71.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-20906 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-20906 | HTTPS FTP |
-Validation report
Summary document | emd_20906_validation.pdf.gz | 622.6 KB | Display | EMDB validaton report |
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Full document | emd_20906_full_validation.pdf.gz | 622.1 KB | Display | |
Data in XML | emd_20906_validation.xml.gz | 17.5 KB | Display | |
Data in CIF | emd_20906_validation.cif.gz | 23 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-20906 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-20906 | HTTPS FTP |
-Related structure data
Related structure data | 6uvaMC 6uunC 6uusC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_20906.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.83 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_20906_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: Adrenomedullin 2 receptor G protein complex with adrenomedullin...
File | emd_20906_additional_1.map | ||||||||||||
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Annotation | Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Adrenomedullin 2 receptor G protein complex with adrenomedullin...
File | emd_20906_additional_2.map | ||||||||||||
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Annotation | Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Adrenomedullin 2 receptor G protein complex with adrenomedullin...
File | emd_20906_additional_3.map | ||||||||||||
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Annotation | Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide focused refinement on receptor, post-processed | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Adrenomedullin 2 receptor G protein complex with adrenomedullin...
File | emd_20906_half_map_1.map | ||||||||||||
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Annotation | Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Adrenomedullin 2 receptor G protein complex with adrenomedullin...
File | emd_20906_half_map_2.map | ||||||||||||
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Annotation | Adrenomedullin 2 receptor G protein complex with adrenomedullin 2 peptide | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : AM2:CLR:RAMP3:GasDN:Gb1:Gg2:Nb35 GPCR Complex
+Supramolecule #1: AM2:CLR:RAMP3:GasDN:Gb1:Gg2:Nb35 GPCR Complex
+Supramolecule #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms sh...
+Supramolecule #3: Nanobody 35
+Supramolecule #4: Protein ADM2
+Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: Nanobody 35
+Macromolecule #5: Receptor activity-modifying protein 3
+Macromolecule #6: Protein ADM2
+Macromolecule #7: Calcitonin gene-related peptide type 1 receptor
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 4 mg/mL |
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Buffer | pH: 7.4 |
Grid | Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Details: unspecified |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 68.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |