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- PDB-7f8y: Crystal structure of the cholecystokinin receptor CCKAR in comple... -

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Basic information

Entry
Database: PDB / ID: 7f8y
TitleCrystal structure of the cholecystokinin receptor CCKAR in complex with devazepide
Componentsfusion protein of Cholecystokinin receptor type A and Endolysin
KeywordsSTRUCTURAL PROTEIN / G protein-coulped receptor / Cholecystokinin receptor CCKAR / devazepide
Function / homology
Function and homology information


cholecystokinin receptor activity / cholecystokinin signaling pathway / regulation of hormone secretion / neuropeptide receptor activity / peptide hormone binding / viral release from host cell by cytolysis / forebrain development / cellular response to hormone stimulus / peptidoglycan catabolic process / Peptide ligand-binding receptors ...cholecystokinin receptor activity / cholecystokinin signaling pathway / regulation of hormone secretion / neuropeptide receptor activity / peptide hormone binding / viral release from host cell by cytolysis / forebrain development / cellular response to hormone stimulus / peptidoglycan catabolic process / Peptide ligand-binding receptors / axonogenesis / peptide binding / neuron migration / cell wall macromolecule catabolic process / lysozyme / lysozyme activity / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / host cell cytoplasm / defense response to bacterium / G protein-coupled receptor signaling pathway / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
Cholecystokinin receptor type A / Cholecystokinin A receptor, N-terminal / Cholecystokinin A receptor, N-terminal domain superfamily / Cholecystokinin A receptor, N-terminal / Cholecystokinin receptor / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme ...Cholecystokinin receptor type A / Cholecystokinin A receptor, N-terminal / Cholecystokinin A receptor, N-terminal domain superfamily / Cholecystokinin A receptor, N-terminal / Cholecystokinin receptor / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Lysozyme-like domain superfamily
Similarity search - Domain/homology
Chem-1OZ / Endolysin / Cholecystokinin receptor type A
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterobacteria phage T4 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsZhang, X. / He, C. / Wang, M. / Zhou, Q. / Yang, D. / Zhu, Y. / Wu, B. / Zhao, Q.
Funding support China, 10items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)21704064 China
National Science Foundation (NSF, China)81773792 China
National Science Foundation (NSF, China)81973373 China
National Science Foundation (NSF, China)31800621 China
National Science Foundation (NSF, China)31770796 China
National Science Foundation (NSF, China)31971178 China
National Science Foundation (NSF, China)81872915 China
National Science Foundation (NSF, China)82073904 China
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)81525024 China
CitationJournal: Nat Chem Biol / Year: 2021
Title: Structures of the human cholecystokinin receptors bound to agonists and antagonists.
Authors: Xuefeng Zhang / Chenglin He / Mu Wang / Qingtong Zhou / Dehua Yang / Ya Zhu / Wenbo Feng / Hui Zhang / Antao Dai / Xiaojing Chu / Jia Wang / Zhenlin Yang / Yi Jiang / Ulrich Sensfuss / ...Authors: Xuefeng Zhang / Chenglin He / Mu Wang / Qingtong Zhou / Dehua Yang / Ya Zhu / Wenbo Feng / Hui Zhang / Antao Dai / Xiaojing Chu / Jia Wang / Zhenlin Yang / Yi Jiang / Ulrich Sensfuss / Qiuxiang Tan / Shuo Han / Steffen Reedtz-Runge / H Eric Xu / Suwen Zhao / Ming-Wei Wang / Beili Wu / Qiang Zhao /
Abstract: Cholecystokinin receptors, CCKR and CCKR, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal ...Cholecystokinin receptors, CCKR and CCKR, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal structures of the human CCKR in complex with different ligands, including one peptide agonist and two small-molecule antagonists, as well as two cryo-electron microscopy structures of CCKR-gastrin in complex with G and G, respectively. These structures reveal the recognition pattern of different ligand types and the molecular basis of peptide selectivity in the cholecystokinin receptor family. By comparing receptor structures in different conformational states, a stepwise activation process of cholecystokinin receptors is proposed. Combined with pharmacological data, our results provide atomic details for differential ligand recognition and receptor activation mechanisms. These insights will facilitate the discovery of potential therapeutics targeting cholecystokinin receptors.
History
DepositionJul 2, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: 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: fusion protein of Cholecystokinin receptor type A and Endolysin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,8592
Polymers60,4501
Non-polymers4081
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area22330 Å2
Unit cell
Length a, b, c (Å)54.780, 72.420, 86.140
Angle α, β, γ (deg.)90.000, 107.284, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein fusion protein of Cholecystokinin receptor type A and Endolysin / CCK-A receptor / CCK-AR / Cholecystokinin-1 receptor / CCK1-R / Lysis protein / Lysozyme / Muramidase


Mass: 60450.367 Da / Num. of mol.: 1 / Mutation: D87N,F130W,R1251G,G1293T,C1336A,I385R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Enterobacteria phage T4 (virus)
Gene: CCKAR, CCKRA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P32238, UniProt: P00720, lysozyme
#2: Chemical ChemComp-1OZ / N-[(3S)-1-methyl-2-oxidanylidene-5-phenyl-3H-1,4-benzodiazepin-3-yl]-1H-indole-2-carboxamide


Mass: 408.452 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H20N4O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist*YM
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: 2.76 Å3/Da / Density % sol: 55.43 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 0.1 M HEPES, pH 7.5, 25% (v/v) PEG400 and 350 mM ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 39065 / % possible obs: 99.3 % / Redundancy: 4.8 % / Biso Wilson estimate: 68.07 Å2 / CC1/2: 0.986 / Net I/σ(I): 5
Reflection shellResolution: 2.5→2.56 Å / Mean I/σ(I) obs: 1 / Num. unique obs: 2194 / CC1/2: 0.679

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSVERSION Jan 26, 2018data reduction
XSCALEVERSION Jan 26, 2018data scaling
PHASER1.19.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ZBQ

5zbq


Resolution: 2.5→29.77 Å / SU ML: 0.4634 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.5385
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2676 3524 9.02 %
Rwork0.2149 35541 -
obs0.2197 39065 89.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 80.06 Å2
Refinement stepCycle: LAST / Resolution: 2.5→29.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3468 0 31 0 3499
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00793576
X-RAY DIFFRACTIONf_angle_d1.10274857
X-RAY DIFFRACTIONf_chiral_restr0.0554571
X-RAY DIFFRACTIONf_plane_restr0.0062593
X-RAY DIFFRACTIONf_dihedral_angle_d16.29171283
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.530.40021350.39231347X-RAY DIFFRACTION87.13
2.53-2.570.35951450.36211398X-RAY DIFFRACTION87.03
2.57-2.610.38551460.34111409X-RAY DIFFRACTION88.35
2.61-2.650.42741280.31771394X-RAY DIFFRACTION88.69
2.65-2.690.34731350.33041381X-RAY DIFFRACTION87.38
2.69-2.740.33741470.3061463X-RAY DIFFRACTION89.69
2.74-2.790.33481380.29831378X-RAY DIFFRACTION89.02
2.79-2.840.35761320.30111427X-RAY DIFFRACTION88.68
2.84-2.90.32431340.28821436X-RAY DIFFRACTION87.81
2.9-2.960.32771370.28051444X-RAY DIFFRACTION92.08
2.96-3.030.36111470.27071471X-RAY DIFFRACTION91.62
3.03-3.110.2841410.26171420X-RAY DIFFRACTION90.6
3.11-3.190.31311400.24731442X-RAY DIFFRACTION90.4
3.19-3.290.28881480.22791466X-RAY DIFFRACTION90.62
3.29-3.390.27781500.22931435X-RAY DIFFRACTION91.46
3.39-3.510.29521280.23991443X-RAY DIFFRACTION90.55
3.51-3.650.30391470.21941439X-RAY DIFFRACTION88.7
3.65-3.820.25941340.20781354X-RAY DIFFRACTION87.27
3.82-4.020.29451430.19181434X-RAY DIFFRACTION90.01
4.02-4.270.231530.1971425X-RAY DIFFRACTION89.97
4.27-4.60.23551440.17591442X-RAY DIFFRACTION90.53
4.6-5.060.25941470.18091426X-RAY DIFFRACTION90.09
5.06-5.790.25551430.21061371X-RAY DIFFRACTION86.81
5.79-7.270.22691480.20781454X-RAY DIFFRACTION91.6
7.28-29.770.20551340.1631442X-RAY DIFFRACTION89.75
Refinement TLS params.Method: refined / Origin x: 8.92821277326 Å / Origin y: 17.7892190846 Å / Origin z: 24.340940478 Å
111213212223313233
T0.516487852149 Å20.0671387261289 Å2-0.014340854785 Å2-0.477442425502 Å20.0146756860076 Å2--0.515209659206 Å2
L0.215196971379 °20.228695396766 °2-0.258559216409 °2--0.0920763494096 °2-0.0103012101912 °2--0.911391475391 °2
S-0.0870713418506 Å °0.0381169190857 Å °0.0458050165167 Å °0.0233837089094 Å °-0.0280275985622 Å °0.0188253363518 Å °0.0138522728184 Å °-0.00784168004447 Å °4.16157560407E-11 Å °
Refinement TLS groupSelection details: all

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