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- PDB-7knu: CryoEM structure of the CGRP receptor with bound CGRP peptide in ... -

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Basic information

Entry
Database: PDB / ID: 7knu
TitleCryoEM structure of the CGRP receptor with bound CGRP peptide in a detergent micelle
Components
  • Calcitonin gene-related peptide 1
  • Calcitonin gene-related peptide type 1 receptor
  • Receptor activity-modifying protein 1
KeywordsSIGNALING PROTEIN / GPCR / CGRP receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


calcitonin gene-related peptide binding / nervous system process involved in regulation of systemic arterial blood pressure / positive regulation of protein glycosylation / amylin receptor activity / amylin receptor complex 1 / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin receptor activity / adrenomedullin binding / adrenomedullin receptor complex ...calcitonin gene-related peptide binding / nervous system process involved in regulation of systemic arterial blood pressure / positive regulation of protein glycosylation / amylin receptor activity / amylin receptor complex 1 / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin receptor activity / adrenomedullin binding / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / calcitonin receptor activity / cellular response to sucrose stimulus / calcitonin gene-related peptide receptor activity / positive regulation of interleukin-1 alpha production / amylin receptor signaling pathway / negative regulation of calcium ion transport into cytosol / regulation of G protein-coupled receptor signaling pathway / G protein-coupled receptor internalization / positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway / positive regulation of macrophage differentiation / negative regulation of smooth muscle contraction / vasculature development / endothelial cell proliferation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / G protein-coupled peptide receptor activity / negative regulation of bone resorption / negative regulation of osteoclast differentiation / leukocyte cell-cell adhesion / response to yeast / coreceptor activity / antifungal humoral response / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / endothelial cell migration / G protein-coupled receptor activity / activation of adenylate cyclase activity / negative regulation of blood pressure / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to hormone stimulus / regulation of cytosolic calcium ion concentration / positive regulation of interleukin-8 production / protein localization to plasma membrane / calcium ion transport / receptor internalization / go:0097755: / intracellular protein transport / hormone activity / positive regulation of smooth muscle cell proliferation / regulation of blood pressure / negative regulation of inflammatory response / protein transport / cell-cell signaling / heart development / antibacterial humoral response / angiogenesis / positive regulation of protein binding / lysosome / cell surface receptor signaling pathway / antimicrobial humoral immune response mediated by antimicrobial peptide / receptor complex / endosome / defense response to Gram-negative bacterium / defense response to Gram-positive bacterium / G protein-coupled receptor signaling pathway / signaling receptor binding / protein-containing complex binding / protein phosphorylation / innate immune response / endoplasmic reticulum / cell surface / integral component of plasma membrane / extracellular space / extracellular region / plasma membrane / cytoplasm
Calcitonin, conserved site / Calcitonin peptide-like / GPCR, family 2, calcitonin receptor family / Calcitonin/adrenomedullin / Calcitonin-like / GPCR family 2, extracellular hormone receptor domain superfamily / GPCR, family 2, secretin-like / RAMP domain superfamily / GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / GPCR, family 2, secretin-like, conserved site ...Calcitonin, conserved site / Calcitonin peptide-like / GPCR, family 2, calcitonin receptor family / Calcitonin/adrenomedullin / Calcitonin-like / GPCR family 2, extracellular hormone receptor domain superfamily / GPCR, family 2, secretin-like / RAMP domain superfamily / GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / GPCR, family 2, secretin-like, conserved site / GPCR, family 2-like / GPCR, family 2, extracellular hormone receptor domain / Calcitonin gene-related peptide / Receptor activity modifying protein
Receptor activity-modifying protein 1 / Calcitonin gene-related peptide 1 / Calcitonin gene-related peptide type 1 receptor
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.49 Å
AuthorsBelousoff, M.J. / Danev, R.
Funding support Australia, 4items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1061044 Australia
National Health and Medical Research Council (NHMRC, Australia)1065410 Australia
National Health and Medical Research Council (NHMRC, Australia)1126857 Australia
National Health and Medical Research Council (NHMRC, Australia)1055134 Australia
CitationJournal: Science / Year: 2021
Title: Structure and dynamics of the CGRP receptor in apo and peptide-bound forms.
Authors: Tracy M Josephs / Matthew J Belousoff / Yi-Lynn Liang / Sarah J Piper / Jianjun Cao / Daniel J Garama / Katie Leach / Karen J Gregory / Arthur Christopoulos / Debbie L Hay / Radostin Danev / ...Authors: Tracy M Josephs / Matthew J Belousoff / Yi-Lynn Liang / Sarah J Piper / Jianjun Cao / Daniel J Garama / Katie Leach / Karen J Gregory / Arthur Christopoulos / Debbie L Hay / Radostin Danev / Denise Wootten / Patrick M Sexton /
Abstract: G protein-coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only limited understanding of the behavior of GPCRs in the apo state ...G protein-coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene-related peptide (CGRP) receptors to determine their cryo-EM structures and complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and 3D variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound, CGRP receptor complex, our work provides important insight into mechanisms of class B1 GPCR activation.
Validation Report
SummaryFull reportAbout validation report
History
DepositionNov 6, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

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Assembly

Deposited unit
E: Receptor activity-modifying protein 1
P: Calcitonin gene-related peptide 1
R: Calcitonin gene-related peptide type 1 receptor


Theoretical massNumber of molelcules
Total (without water)77,1393
Polymers77,1393
Non-polymers00
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5410 Å2
ΔGint-42 kcal/mol
Surface area24780 Å2

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Components

#1: Protein Receptor activity-modifying protein 1 / Calcitonin-receptor-like receptor activity-modifying protein 1 / CRLR activity-modifying protein 1


Mass: 17066.701 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAMP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O60894
#2: Protein/peptide Calcitonin gene-related peptide 1 / / Alpha-type CGRP / Calcitonin gene-related peptide I / CGRP-I


Mass: 3797.347 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P06881
#3: Protein Calcitonin gene-related peptide type 1 receptor / CGRP type 1 receptor / Calcitonin receptor-like receptor


Mass: 56274.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALCRL, CGRPR / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16602

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1CGRP receptor bound to CGRP and RAMP1COMPLEX#1-#30MULTIPLE SOURCES
2CGRP receptor with RAMP1COMPLEX#1, #31RECOMBINANT
3Calcitonin gene-related peptide 1COMPLEX#21SYNTHETIC
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 57.3 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 284400 / Symmetry type: POINT
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0023918
ELECTRON MICROSCOPYf_angle_d0.5265334
ELECTRON MICROSCOPYf_dihedral_angle_d21.639503
ELECTRON MICROSCOPYf_chiral_restr0.037599
ELECTRON MICROSCOPYf_plane_restr0.005653

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