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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


nervous system process involved in regulation of systemic arterial blood pressure / calcitonin gene-related peptide binding / adrenomedullin binding / CGRP receptor complex / cellular response to sucrose stimulus / positive regulation of protein glycosylation / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity ...nervous system process involved in regulation of systemic arterial blood pressure / calcitonin gene-related peptide binding / adrenomedullin binding / CGRP receptor complex / cellular response to sucrose stimulus / positive regulation of protein glycosylation / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity / calcitonin receptor activity / calcitonin gene-related peptide receptor signaling pathway / vascular associated smooth muscle cell proliferation / positive regulation of interleukin-1 alpha production / calcitonin gene-related peptide receptor activity / negative regulation of calcium ion transport into cytosol / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / positive regulation of macrophage differentiation / Calcitonin-like ligand receptors / regulation of G protein-coupled receptor signaling pathway / vasculature development / G protein-coupled receptor internalization / endothelial cell proliferation / negative regulation of bone resorption / leukocyte cell-cell adhesion / negative regulation of osteoclast differentiation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / endothelial cell migration / regulation of cytosolic calcium ion concentration / activation of adenylate cyclase activity / cellular response to hormone stimulus / coreceptor activity / negative regulation of blood pressure / positive regulation of vascular associated smooth muscle cell proliferation / protein localization to plasma membrane / positive regulation of interleukin-8 production / intracellular protein transport / G protein-coupled receptor activity / hormone activity / receptor internalization / regulation of blood pressure / adenylate cyclase-activating G protein-coupled receptor signaling pathway / vasodilation / calcium ion transport / protein transport / cell-cell signaling / heart development / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (s) signalling events / angiogenesis / lysosome / receptor complex / cell surface receptor signaling pathway / endosome / G protein-coupled receptor signaling pathway / protein phosphorylation / signaling receptor binding / protein-containing complex binding / cell surface / endoplasmic reticulum / extracellular space / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
Calcitonin gene-related peptide / GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / Receptor activity modifying protein / RAMP domain superfamily / Receptor activity modifying family / GPCR, family 2, calcitonin receptor family / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. ...Calcitonin gene-related peptide / GPCR, family 2, calcitonin gene-related peptide, type 1 receptor / Receptor activity modifying protein / RAMP domain superfamily / Receptor activity modifying family / GPCR, family 2, calcitonin receptor family / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. / calcitonin / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2.
Similarity search - Domain/homology
Receptor activity-modifying protein 1 / Calcitonin gene-related peptide 1 / Calcitonin gene-related peptide type 1 receptor
Similarity search - Component
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 a limited understanding of the behavior of GPCRs in the apo ...G protein-coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only a 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 from insect cells to determine their cryo-electron microscopy (cryo-EM) structures, and we complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry and three-dimensional variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound CGRP receptor complex, our work provides insight into the mechanisms of class B1 GPCR activation.
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
Revision 1.2Apr 21, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation_author.identifier_ORCID
Revision 1.3Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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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
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
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
Has protein modificationY

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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 RAMP1COMPLEXall0MULTIPLE 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 FIELD
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
Refine-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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