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- PDB-6umg: Crystal structure of erenumab Fab bound to the extracellular doma... -

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Basic information

Entry
Database: PDB / ID: 6umg
TitleCrystal structure of erenumab Fab bound to the extracellular domain of CGRP receptor
Components
  • Calcitonin gene-related peptide type 1 receptor
  • Receptor activity-modifying protein 1
  • erenumab Fab heavy chain, IgG1
  • erenumab Fab light chain, IgG1
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / Class B GPCR / Complex / Fragment antigen binding / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


calcitonin gene-related peptide binding / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin binding / positive regulation of protein glycosylation / cellular response to sucrose stimulus / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity ...calcitonin gene-related peptide binding / CGRP receptor complex / calcitonin gene-related peptide receptor signaling pathway / adrenomedullin binding / positive regulation of protein glycosylation / cellular response to sucrose stimulus / 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 G protein-coupled receptor signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / coreceptor activity / cellular response to hormone stimulus / positive regulation of vascular associated smooth muscle cell proliferation / G protein-coupled receptor activity / protein localization to plasma membrane / intracellular protein transport / adenylate cyclase-activating G protein-coupled receptor signaling pathway / receptor internalization / calcium ion transport / protein transport / heart development / G alpha (s) signalling events / angiogenesis / lysosome / cell surface receptor signaling pathway / receptor complex / endosome / G protein-coupled receptor signaling pathway / cell surface / endoplasmic reticulum / plasma membrane / cytoplasm
Similarity search - Function
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 / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors ...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 / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / 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 type 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsMohr, C.
CitationJournal: Cell Rep / Year: 2020
Title: Molecular Insight into Recognition of the CGRPR Complex by Migraine Prevention Therapy Aimovig (Erenumab).
Authors: Garces, F. / Mohr, C. / Zhang, L. / Huang, C.S. / Chen, Q. / King, C. / Xu, C. / Wang, Z.
History
DepositionOct 9, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
H: erenumab Fab heavy chain, IgG1
L: erenumab Fab light chain, IgG1
C: Calcitonin gene-related peptide type 1 receptor
R: Receptor activity-modifying protein 1
h: erenumab Fab heavy chain, IgG1
l: erenumab Fab light chain, IgG1
c: Calcitonin gene-related peptide type 1 receptor
r: Receptor activity-modifying protein 1


Theoretical massNumber of molelcules
Total (without water)156,8438
Polymers156,8438
Non-polymers00
Water1,71195
1
H: erenumab Fab heavy chain, IgG1
L: erenumab Fab light chain, IgG1
C: Calcitonin gene-related peptide type 1 receptor
R: Receptor activity-modifying protein 1


Theoretical massNumber of molelcules
Total (without water)78,4214
Polymers78,4214
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8090 Å2
ΔGint-40 kcal/mol
Surface area28940 Å2
MethodPISA
2
h: erenumab Fab heavy chain, IgG1
l: erenumab Fab light chain, IgG1
c: Calcitonin gene-related peptide type 1 receptor
r: Receptor activity-modifying protein 1


Theoretical massNumber of molelcules
Total (without water)78,4214
Polymers78,4214
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7750 Å2
ΔGint-42 kcal/mol
Surface area28690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.464, 112.520, 77.254
Angle α, β, γ (deg.)90.000, 91.840, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Antibody erenumab Fab heavy chain, IgG1


Mass: 25483.525 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pTT5 / Cell line (production host): HEK 293-6E / Production host: Homo sapiens (human)
#2: Antibody erenumab Fab light chain, IgG1


Mass: 22827.324 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pTT5 / Cell line (production host): HEK 293-6E / Production host: Homo sapiens (human)
#3: Protein Calcitonin gene-related peptide type 1 receptor / CGRP type 1 receptor / Calcitonin receptor-like receptor


Mass: 16269.885 Da / Num. of mol.: 2 / Fragment: extracellular domain (UNP residues 23-133)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALCRL, CGRPR / Plasmid: pDEST 17 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q16602
#4: Protein Receptor activity-modifying protein 1 / Calcitonin-receptor-like receptor activity-modifying protein 1 / CRLR activity-modifying protein 1


Mass: 13840.678 Da / Num. of mol.: 2 / Fragment: extracellular domain (UNP residues 26-117)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAMP1 / Plasmid: pDEST 17 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60894
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 1.95 Å3/Da / Density % sol: 36.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.12 M ethylene glycols, 0.1 M HEPES:MOPS, pH 7.5, 37.5% MPD + PEG1000 + PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: May 26, 2015 / Details: VariMax HF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.7→30 Å / Num. obs: 33135 / % possible obs: 99.9 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.088 / Rrim(I) all: 0.165 / Χ2: 1 / Net I/σ(I): 5.6
Reflection shell

Χ2: 1 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.7-2.83.30.5932.0732740.6980.3760.70499.9
2.8-2.913.30.49933070.7650.3150.592100
2.91-3.043.40.37133220.8520.2330.44100
3.04-3.23.40.27933080.9180.1760.33100
3.2-3.43.40.19332970.9520.1210.228100
3.4-3.663.40.15133130.9550.0960.179100
3.66-4.033.40.12133140.9810.0760.143100
4.03-4.613.40.08133280.9910.0510.096100
4.61-5.83.40.0833260.9920.0510.09599.9
5.8-303.40.06833460.9950.0430.0898.8

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Processing

Software
NameVersionClassification
CrystalCleardata collection
DENZOdata reduction
HKL-2000data reduction
SCALEPACKdata scaling
HKL-2000data scaling
PHASERphasing
MOLREPphasing
REFMAC5.8.0073refinement
Cootmodel building
PHENIXmodel building
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3N7P

3n7p


Resolution: 2.7→30 Å / Cor.coef. Fo:Fc: 0.895 / Cor.coef. Fo:Fc free: 0.864 / SU B: 18.626 / SU ML: 0.365 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.433
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2819 1555 4.7 %RANDOM
Rwork0.2448 ---
obs0.2466 31528 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 76.64 Å2 / Biso mean: 36.707 Å2 / Biso min: 13.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.75 Å2-0 Å20.17 Å2
2---0.19 Å2-0 Å2
3----0.56 Å2
Refinement stepCycle: final / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9718 0 0 95 9813
Biso mean---26.67 -
Num. residues----1259
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.029983
X-RAY DIFFRACTIONr_bond_other_d0.0020.029020
X-RAY DIFFRACTIONr_angle_refined_deg0.8991.93513591
X-RAY DIFFRACTIONr_angle_other_deg0.817320826
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.17351247
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.01624.269431
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.907151553
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5641546
X-RAY DIFFRACTIONr_chiral_restr0.0530.21477
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.02111379
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022329
LS refinement shellResolution: 2.7→2.77 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.38 125 -
Rwork0.332 2302 -
all-2427 -
obs--99.75 %

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