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- PDB-7p0i: Crystal structure of a CGRP receptor ectodomain heterodimer bound... -

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Basic information

Entry
Database: PDB / ID: 7p0i
TitleCrystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor Compound 13
ComponentsMaltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor
KeywordsMEMBRANE PROTEIN / GPCR / CGRP / ectodomain / inhibitor / macrocycle
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 / maltose transport / maltodextrin transmembrane transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / 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 / angiogenesis / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / 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-7IU / Receptor activity-modifying protein 1 / Maltose/maltodextrin-binding periplasmic protein / Calcitonin gene-related peptide type 1 receptor
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsSouthall, S.M.
CitationJournal: Acs Chem Neurosci / Year: 2022
Title: Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes.
Authors: Cansfield, A.D. / Ator, M.A. / Banerjee, J. / Bestwick, M. / Bortolato, A. / Brown, G.A. / Brown, J. / Butkovic, K. / Cansfield, J.E. / Christopher, J.A. / Congreve, M. / Cseke, G. / ...Authors: Cansfield, A.D. / Ator, M.A. / Banerjee, J. / Bestwick, M. / Bortolato, A. / Brown, G.A. / Brown, J. / Butkovic, K. / Cansfield, J.E. / Christopher, J.A. / Congreve, M. / Cseke, G. / Deflorian, F. / Dugan, B. / Hunjadi, M.P. / Hutinec, A. / Inturi, T.K. / Landek, G. / Mason, J. / O'Brien, A. / Ott, G.R. / Rupcic, R. / Saxty, G. / Southall, S.M. / Zadravec, R. / Watson, S.P.
History
DepositionJun 29, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 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 1.2Nov 20, 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)67,6995
Polymers66,3611
Non-polymers1,3384
Water3,423190
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1540 Å2
ΔGint13 kcal/mol
Surface area25010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.195, 77.633, 97.983
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 66360.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (strain K12) (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-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-7IU / (1S,20E)-10-(benzofuran-3-ylmethyl)-12-methyl-15,18-dioxa-5,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3(30),4,6,20,22(29),23,25(28)-heptaene-8,11,27-trione


Mass: 607.656 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H33N5O6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / 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: 2.04 Å3/Da / Density % sol: 39.71 %
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: 0.96862 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 17, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96862 Å / Relative weight: 1
ReflectionResolution: 2.3→41.43 Å / Num. obs: 24809 / % possible obs: 100 % / Redundancy: 7.3 % / Biso Wilson estimate: 34.03 Å2 / CC1/2: 0.987 / Rmerge(I) obs: 0.332 / Rpim(I) all: 0.132 / Rrim(I) all: 0.357 / Net I/σ(I): 6.2 / Num. measured all: 180617
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.3-2.387.42.4031766223910.2810.9492.5871100
8.91-41.436.10.04830034930.9980.0210.05324.598.9

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
PHENIX1.19.1_4122refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RWF

4rwf


Resolution: 2.3→29.69 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 27.23 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2509 1216 4.91 %
Rwork0.1968 23526 -
obs0.1996 24742 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 159.31 Å2 / Biso mean: 40.9462 Å2 / Biso min: 18.56 Å2
Refinement stepCycle: final / Resolution: 2.3→29.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4518 0 94 190 4802
Biso mean--40.9 38.07 -
Num. residues----571
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.3-2.390.35141060.311825872693
2.39-2.50.34881180.285625982716
2.5-2.630.31821400.261825752715
2.63-2.80.29121310.237225662697
2.8-3.010.31031430.228125872730
3.01-3.320.28761300.202826012731
3.32-3.80.23121330.166626392772
3.8-4.780.19711630.145426182781
4.78-29.690.21211520.17227552907
Refinement TLS params.Method: refined / Origin x: 12.6709 Å / Origin y: -2.27 Å / Origin z: -12.8279 Å
111213212223313233
T0.1997 Å2-0.0122 Å2-0.0327 Å2-0.2563 Å20.014 Å2--0.2051 Å2
L0.494 °2-0.3816 °2-0.48 °2-1.0757 °20.6774 °2--0.9275 °2
S0.0484 Å °0.0147 Å °0.0432 Å °0.0143 Å °-0.0899 Å °0.018 Å °-0.0141 Å °-0.0916 Å °0.0464 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 2201
2X-RAY DIFFRACTION1allD1 - 2
3X-RAY DIFFRACTION1allB1
4X-RAY DIFFRACTION1allS1 - 215

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