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- EMDB-22963: CryoEM structure of the CGRP receptor with bound CGRP peptide in ... -

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Basic information

Entry
Database: EMDB / ID: EMD-22963
TitleCryoEM structure of the CGRP receptor with bound CGRP peptide in a detergent micelle
Map data
SampleCGRP receptor bound to CGRP and RAMP1
  • CGRP receptor with RAMP1
  • (Calcitonin gene-related peptide ...) x 3
  • Receptor activity-modifying protein 1
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.49 Å
AuthorsBelousoff MJ / Danev R
Funding support Australia, 4 items
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 ReportSummary, Full report, XML, About validation report
History
DepositionNov 6, 2020-
Header (metadata) releaseFeb 24, 2021-
Map releaseFeb 24, 2021-
UpdateMar 3, 2021-
Current statusMar 3, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.235
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.235
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7knu
  • Surface level: 0.235
  • Imaged by UCSF Chimera
  • Download
  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7knu
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22963.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 240 pix.
= 199.2 Å
0.83 Å/pix.
x 240 pix.
= 199.2 Å
0.83 Å/pix.
x 240 pix.
= 199.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.235 / Movie #1: 0.235
Minimum - Maximum-0.5243779 - 0.8792717
Average (Standard dev.)-0.00069612375 (±0.033403132)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 199.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.830.830.83
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z199.200199.200199.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.5240.879-0.001

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Supplemental data

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Segmentation: #1

Fileemd_22963_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Additional map: Map refined using SIDESplitter reconstruction in combination with...

Fileemd_22963_additional_1.map
AnnotationMap refined using SIDESplitter reconstruction in combination with RELION maximum likelihood.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map 1

Fileemd_22963_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map 2

Fileemd_22963_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire CGRP receptor bound to CGRP and RAMP1

EntireName: CGRP receptor bound to CGRP and RAMP1 / Number of components: 6

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Component #1: protein, CGRP receptor bound to CGRP and RAMP1

ProteinName: CGRP receptor bound to CGRP and RAMP1 / Recombinant expression: No

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Component #2: protein, CGRP receptor with RAMP1

ProteinName: CGRP receptor with RAMP1 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #3: protein, Calcitonin gene-related peptide 1

ProteinName: Calcitonin gene-related peptide 1 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)

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Component #4: protein, Receptor activity-modifying protein 1

ProteinName: Receptor activity-modifying protein 1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 17.066701 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #5: protein, Calcitonin gene-related peptide 1

ProteinName: Calcitonin gene-related peptide 1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 3.797347 kDa
SourceSpecies: Homo sapiens (human)

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Component #6: protein, Calcitonin gene-related peptide type 1 receptor

ProteinName: Calcitonin gene-related peptide type 1 receptor / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 56.27452 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 57.3 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 284400
3D reconstructionResolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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