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- PDB-8ax5: Crystal structure of a CGRP receptor ectodomain heterodimer bound... -

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Basic information

Entry
Database: PDB / ID: 8ax5
TitleCrystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0029881
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 / Chem-OKU / 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: 2.75 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

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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
Water1,42379
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1170 Å2
ΔGint12 kcal/mol
Surface area23940 Å2
Unit cell
Length a, b, c (Å)71.687, 78.534, 97.926
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-OKU / (1~{R},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-3,5,7(30),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 / Polyethylene glycol


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


Mass: 18.015 Da / Num. of mol.: 79 / Source method: isolated from a natural source / Formula: H2O
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: 2.08 Å3/Da / Density % sol: 40.84 %
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: Aug 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 2.75→48.96 Å / Num. obs: 14328 / % possible obs: 96.6 % / Redundancy: 6.8 % / Biso Wilson estimate: 39.82 Å2 / CC1/2: 0.971 / Net I/σ(I): 5.4
Reflection shellResolution: 2.75→2.9 Å / Num. unique obs: 2100 / CC1/2: 0.397

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RWG

4rwg


Resolution: 2.75→48.96 Å / SU ML: 0.3924 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.0669
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.277 1207 4.67 %
Rwork0.2201 24639 -
obs0.2229 14288 93.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.62 Å2
Refinement stepCycle: LAST / Resolution: 2.75→48.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4343 0 82 79 4504
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00254564
X-RAY DIFFRACTIONf_angle_d0.47946209
X-RAY DIFFRACTIONf_chiral_restr0.039659
X-RAY DIFFRACTIONf_plane_restr0.0036797
X-RAY DIFFRACTIONf_dihedral_angle_d15.12121665
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-2.860.38291220.29732783X-RAY DIFFRACTION94.23
2.86-2.990.35841370.29732786X-RAY DIFFRACTION94.78
2.99-3.150.33221410.28312808X-RAY DIFFRACTION94.22
3.15-3.350.37041470.26352697X-RAY DIFFRACTION94.02
3.35-3.60.29271280.23242728X-RAY DIFFRACTION91.57
3.6-3.970.24881360.20382663X-RAY DIFFRACTION90.76
3.97-4.540.2331510.16922717X-RAY DIFFRACTION93.12
4.54-5.720.24111250.18672738X-RAY DIFFRACTION93.17
5.72-48.960.22341200.19352719X-RAY DIFFRACTION91.91
Refinement TLS params.Method: refined / Origin x: 12.5373658726 Å / Origin y: -3.81624960015 Å / Origin z: -13.2269188863 Å
111213212223313233
T0.275660067585 Å2-0.00992490660979 Å2-0.00822739442592 Å2-0.290218728387 Å20.0253595155736 Å2--0.287728241219 Å2
L0.239478510653 °2-0.216758388463 °2-0.299778144356 °2-0.807422393262 °20.728519504261 °2--0.712076988182 °2
S0.00207361183735 Å °0.0431278569957 Å °0.0569713911483 Å °0.0453087308297 Å °-0.0296957826133 Å °-0.023198965521 Å °0.0740341594836 Å °0.00247402285123 Å °1.59896949012E-5 Å °
Refinement TLS groupSelection details: all

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