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- PDB-8ax7: Crystal structure of a CGRP receptor ectodomain heterodimer bound... -

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Basic information

Entry
Database: PDB / ID: 8ax7
TitleCrystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0031448
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 / 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 / detection of maltose stimulus / maltose transport complex / maltose binding / maltose transport / maltodextrin transmembrane transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / carbohydrate transport / carbohydrate transmembrane transporter activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / coreceptor activity / cellular response to hormone stimulus / positive regulation of vascular associated smooth muscle cell proliferation / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / protein localization to plasma membrane / G protein-coupled receptor activity / intracellular protein transport / receptor internalization / adenylate cyclase-activating G protein-coupled receptor signaling pathway / calcium ion transport / protein transport / heart development / outer membrane-bounded periplasmic space / G alpha (s) signalling events / angiogenesis / periplasmic space / lysosome / cell surface receptor signaling pathway / 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. / 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. / 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 / ACETATE ION / Chem-OL0 / 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: 1.65 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

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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)67,6377
Polymers66,2881
Non-polymers1,3486
Water10,935607
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1790 Å2
ΔGint9 kcal/mol
Surface area24900 Å2
Unit cell
Length a, b, c (Å)70.742, 76.715, 97.781
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

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Protein / Sugars , 2 types, 2 molecules A

#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

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Non-polymers , 4 types, 612 molecules

#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-OL0 / (1~{S},10~{R},20~{E})-10-[(1,7-dimethylindazol-5-yl)methyl]-12-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: 634.724 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H38N6O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 607 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2 Å3/Da / Density % sol: 38.54 %
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: Mar 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 1.65→48.89 Å / Num. obs: 163794 / % possible obs: 96.9 % / Redundancy: 5.4 % / Biso Wilson estimate: 16.6 Å2 / CC1/2: 0.997 / Rpim(I) all: 0.064 / Net I/σ(I): 9.3
Reflection shellResolution: 1.65→1.68 Å / Num. unique obs: 17394 / CC1/2: 0.387 / Rpim(I) all: 0.669

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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: 1.65→33.72 Å / SU ML: 0.2278 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 24.4523
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2508 3134 5.01 %
Rwork0.204 59423 -
obs0.2064 62557 96.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.86 Å2
Refinement stepCycle: LAST / Resolution: 1.65→33.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4480 0 95 607 5182
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00524753
X-RAY DIFFRACTIONf_angle_d0.74766472
X-RAY DIFFRACTIONf_chiral_restr0.0495689
X-RAY DIFFRACTIONf_plane_restr0.0063834
X-RAY DIFFRACTIONf_dihedral_angle_d19.08931734
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.680.35141280.29522785X-RAY DIFFRACTION100
1.68-1.70.35931550.2822734X-RAY DIFFRACTION99.66
1.7-1.730.32241410.27942743X-RAY DIFFRACTION99.31
1.73-1.760.3031400.26042732X-RAY DIFFRACTION99.48
1.76-1.80.33021320.26192756X-RAY DIFFRACTION99.48
1.8-1.830.27551370.23632762X-RAY DIFFRACTION99.62
1.83-1.870.27851500.23232744X-RAY DIFFRACTION99.25
1.87-1.920.281480.21712748X-RAY DIFFRACTION98.97
1.92-1.970.26751420.22212714X-RAY DIFFRACTION98.01
1.97-2.020.27441660.20882670X-RAY DIFFRACTION97.52
2.02-2.080.2481360.19432683X-RAY DIFFRACTION96.51
2.08-2.150.2621660.19312604X-RAY DIFFRACTION95.32
2.15-2.220.24521290.19512616X-RAY DIFFRACTION93.62
2.22-2.310.23331270.19432562X-RAY DIFFRACTION92.31
2.31-2.420.26321350.19672589X-RAY DIFFRACTION92.65
2.42-2.540.24411480.19842568X-RAY DIFFRACTION92.6
2.54-2.70.2481250.1952536X-RAY DIFFRACTION90.48
2.7-2.910.24321310.19512629X-RAY DIFFRACTION93.24
2.91-3.20.24791510.19422685X-RAY DIFFRACTION95.23
3.21-3.670.21591500.17692771X-RAY DIFFRACTION97.63
3.67-4.620.2111300.17152819X-RAY DIFFRACTION97.68
4.62-33.720.24021670.21952973X-RAY DIFFRACTION99.52
Refinement TLS params.Method: refined / Origin x: 12.6020627047 Å / Origin y: -2.97097567417 Å / Origin z: -13.1092252761 Å
111213212223313233
T0.171101194098 Å2-0.00683884751094 Å2-0.00367220392659 Å2-0.186665617382 Å20.0110488529579 Å2--0.180566869497 Å2
L0.209239677961 °2-0.157931958267 °2-0.105790992955 °2-0.492322474503 °20.295680339995 °2--0.456407550234 °2
S-0.0046638600646 Å °-0.00707898890284 Å °0.015716571085 Å °0.0194118264582 Å °-0.00494838975348 Å °0.00331939070879 Å °0.0224770839909 Å °-0.00589105403552 Å °0.00922944599194 Å °
Refinement TLS groupSelection details: all

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