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- PDB-8ax6: Crystal structure of a CGRP receptor ectodomain heterodimer bound... -

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Basic information

Entry
Database: PDB / ID: 8ax6
TitleCrystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0029882
ComponentsMaltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor
KeywordsMEMBRANE PROTEIN / CGRP / CGRPR / ectodomain / RAMP / macrocycle / macrocyclic
Function / homology
Function and homology information


calcitonin gene-related peptide binding / cellular response to sucrose stimulus / adrenomedullin binding / CGRP receptor complex / : / adrenomedullin receptor activity / adrenomedullin receptor complex / adrenomedullin receptor signaling pathway / amylin receptor activity / calcitonin receptor activity ...calcitonin gene-related peptide binding / cellular response to sucrose stimulus / adrenomedullin binding / CGRP receptor complex / : / 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 / calcitonin gene-related peptide receptor activity / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / regulation of G protein-coupled receptor signaling pathway / detection of maltose stimulus / maltose transport complex / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / maltose transport / maltodextrin transmembrane transport / cellular response to hormone stimulus / coreceptor activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / positive regulation of vascular associated smooth muscle cell proliferation / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / protein localization to plasma membrane / intracellular protein transport / G protein-coupled receptor activity / receptor internalization / adenylate cyclase-activating G protein-coupled receptor signaling pathway / calcium ion transport / protein transport / outer membrane-bounded periplasmic space / heart development / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / angiogenesis / G alpha (s) signalling events / periplasmic space / cell surface receptor signaling pathway / lysosome / receptor complex / endosome / G protein-coupled receptor signaling pathway / DNA damage response / cell surface / endoplasmic reticulum / membrane / 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. / : / 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. / : / 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. / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
alpha-maltose / Chem-OP9 / Receptor activity-modifying protein 1 / Maltose/maltodextrin-binding periplasmic protein / Calcitonin gene-related peptide type 1 receptor
Similarity search - Component
Biological speciesEscherichia coli K-12 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsSouthall, S.M. / Watson, S.P.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Not funded United Kingdom
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.
Authors: Southall, S.M. / Banerjee, J. / Brown, J. / Butkovic, K. / Cansfield, A.D. / Cansfield, J.E. / Congreve, M.S. / Cseke, G. / Deflorian, F. / Hunjadi, M.P. / Hutinec, A. / Inturi, T.K. / ...Authors: Southall, S.M. / Banerjee, J. / Brown, J. / Butkovic, K. / Cansfield, A.D. / Cansfield, J.E. / Congreve, M.S. / Cseke, G. / Deflorian, F. / Hunjadi, M.P. / Hutinec, A. / Inturi, T.K. / Rupcic, R. / Saxty, G. / Watson, S.P.
History
DepositionAug 30, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 7, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,4464
Polymers66,2881
Non-polymers1,1573
Water9,026501
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1150 Å2
ΔGint12 kcal/mol
Surface area24890 Å2
Unit cell
Length a, b, c (Å)71.215, 76.356, 96.646
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Calcitonin-receptor-like ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Calcitonin-receptor-like receptor activity-modifying protein 1 / CRLR activity-modifying protein 1 / CGRP type 1 receptor / Calcitonin receptor-like receptor


Mass: 66288.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Homo sapiens (human)
Strain: K12 / Gene: malE, b4034, JW3994, RAMP1, CALCRL, CGRPR / Production host: Homo sapiens (human)
References: UniProt: P0AEX9, UniProt: O60894, UniProt: Q16602
#2: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1a_1-5]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}LINUCSPDB-CARE
#3: Chemical ChemComp-OP9 / (1~{S},10~{R},20~{E})-12-methyl-10-[(7-methyl-2~{H}-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.1^{1,4}.1^{3,7}.0^{25,28}]hentriaconta-3(30),4,6,20,22,24,28-heptaene-8,11,27-trione


Mass: 620.698 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H36N6O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 501 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.98 Å3/Da / Density % sol: 37.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.1 M BIS-TRIS PH 5.5, 0.1 M AMMONIUM ACETATE, 15 % PEG 10,000

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96861 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 29, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 1.9→45.85 Å / Num. obs: 41130 / % possible obs: 96.9 % / Redundancy: 4.1 % / Biso Wilson estimate: 16.52 Å2 / CC1/2: 0.962 / Rpim(I) all: 0.125 / Net I/σ(I): 4.2
Reflection shellResolution: 1.9→1.94 Å / Num. unique obs: 2554 / CC1/2: 0.536 / Rpim(I) all: 0.508

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RWG

4rwg


Resolution: 1.9→29.96 Å / SU ML: 0.2322 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.5513
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2445 2059 5.07 %
Rwork0.1956 38560 -
obs0.1981 40619 96.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.45 Å2
Refinement stepCycle: LAST / Resolution: 1.9→29.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4477 0 82 501 5060
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00354760
X-RAY DIFFRACTIONf_angle_d0.66126494
X-RAY DIFFRACTIONf_chiral_restr0.0428694
X-RAY DIFFRACTIONf_plane_restr0.0045837
X-RAY DIFFRACTIONf_dihedral_angle_d18.07411751
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.940.32041470.24652490X-RAY DIFFRACTION95.82
1.94-1.990.25061270.22072582X-RAY DIFFRACTION98.4
1.99-2.050.23961420.2152608X-RAY DIFFRACTION98.35
2.05-2.110.27821350.21112597X-RAY DIFFRACTION98.2
2.11-2.170.29991270.19772581X-RAY DIFFRACTION97.69
2.17-2.250.24391350.19732559X-RAY DIFFRACTION96.94
2.25-2.340.29521370.19562508X-RAY DIFFRACTION94.9
2.34-2.450.27331540.19972513X-RAY DIFFRACTION94.78
2.45-2.580.25631350.19892485X-RAY DIFFRACTION94.62
2.58-2.740.29441120.18582606X-RAY DIFFRACTION95.57
2.74-2.950.23511400.18512581X-RAY DIFFRACTION97.49
2.95-3.250.24151320.18432636X-RAY DIFFRACTION97.29
3.25-3.720.21421380.17242598X-RAY DIFFRACTION96.88
3.72-4.680.19281600.16972571X-RAY DIFFRACTION95.09
4.68-29.960.22741380.22972645X-RAY DIFFRACTION92.27
Refinement TLS params.Method: refined / Origin x: 12.6665674404 Å / Origin y: -2.94585280184 Å / Origin z: -12.8488802129 Å
111213212223313233
T0.108736328777 Å2-0.00550059181987 Å2-0.00691118448549 Å2-0.132437314119 Å20.0111319916084 Å2--0.12175580102 Å2
L0.205458058957 °2-0.133722958944 °2-0.140542533323 °2-0.470719411055 °20.250554361592 °2--0.513550036814 °2
S0.00525775861502 Å °-0.0193540421222 Å °0.019552983439 Å °0.0105976510222 Å °-0.0150105271883 Å °-0.00315076312903 Å °0.00547692601292 Å °0.00108711239417 Å °0.00594199545922 Å °
Refinement TLS groupSelection details: all

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