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- PDB-8xgy: Crystal structure of human Golgi resident glutaminyl cyclase in c... -

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Basic information

Entry
Database: PDB / ID: 8xgy
TitleCrystal structure of human Golgi resident glutaminyl cyclase in complex with (R,Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-((1-acetylpyrrolidin-3-yl)oxy)indolin-2-one
ComponentsGlutaminyl-peptide cyclotransferase
KeywordsTRANSFERASE / inhibitor / complex
Function / homology
Function and homology information


peptidyl-pyroglutamic acid biosynthetic process, using glutaminyl-peptide cyclotransferase / glutaminyl-peptide cyclotransferase / glutaminyl-peptide cyclotransferase activity / protein modification process / specific granule lumen / tertiary granule lumen / ficolin-1-rich granule lumen / Neutrophil degranulation / extracellular exosome / zinc ion binding / extracellular region
Similarity search - Function
M28 Zn-Peptidase Glutaminyl Cyclase / Glutaminyl-peptide cyclotransferase-like / Peptidase M28 / Peptidase family M28
Similarity search - Domain/homology
: / Glutaminyl-peptide cyclotransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsLi, G.-B. / Wang, X.-Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82122065;82073698 China
CitationJournal: J.Med.Chem. / Year: 2024
Title: X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.
Authors: Mou, J. / Ning, X.L. / Wang, X.Y. / Hou, S.Y. / Meng, F.B. / Zhou, C. / Wu, J.W. / Li, C. / Jia, T. / Wu, X. / Wu, Y. / Chen, Y. / Li, G.B.
History
DepositionDec 16, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Glutaminyl-peptide cyclotransferase
A: Glutaminyl-peptide cyclotransferase
C: Glutaminyl-peptide cyclotransferase
D: Glutaminyl-peptide cyclotransferase
E: Glutaminyl-peptide cyclotransferase
F: Glutaminyl-peptide cyclotransferase
G: Glutaminyl-peptide cyclotransferase
H: Glutaminyl-peptide cyclotransferase
I: Glutaminyl-peptide cyclotransferase
J: Glutaminyl-peptide cyclotransferase
K: Glutaminyl-peptide cyclotransferase
L: Glutaminyl-peptide cyclotransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)456,13536
Polymers450,68912
Non-polymers5,44624
Water37821
1
B: Glutaminyl-peptide cyclotransferase
A: Glutaminyl-peptide cyclotransferase
C: Glutaminyl-peptide cyclotransferase
D: Glutaminyl-peptide cyclotransferase
E: Glutaminyl-peptide cyclotransferase
F: Glutaminyl-peptide cyclotransferase
G: Glutaminyl-peptide cyclotransferase
H: Glutaminyl-peptide cyclotransferase
I: Glutaminyl-peptide cyclotransferase
J: Glutaminyl-peptide cyclotransferase
K: Glutaminyl-peptide cyclotransferase
hetero molecules

L: Glutaminyl-peptide cyclotransferase
hetero molecules


  • defined by author&software
  • 456 kDa, 12 polymers
Theoretical massNumber of molelcules
Total (without water)456,13536
Polymers450,68912
Non-polymers5,44624
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x+1/2,-y,z-1/21
Buried area28290 Å2
ΔGint-120 kcal/mol
Surface area135320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.722, 217.245, 242.303
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Glutaminyl-peptide cyclotransferase / Glutaminyl cyclase / QC / sQC / Glutaminyl-tRNA cyclotransferase / Glutamyl cyclase / EC


Mass: 37557.398 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: QPCT / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q16769, glutaminyl-peptide cyclotransferase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-A1D5C / (3~{Z})-3-(1~{H}-benzimidazol-5-ylmethylidene)-4-[(3~{R})-1-ethanoylpyrrolidin-3-yl]oxy-1~{H}-indol-2-one


Mass: 388.419 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C22H20N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.44 Å3/Da / Density % sol: 49.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 12% -16% PEG 4000, 0.2M MgCl2, 0.1M Tris HCl, pH 8.5

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Data collection

DiffractionMean temperature: 195 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 25, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.81→161.75 Å / Num. obs: 108524 / % possible obs: 100 % / Redundancy: 6.7 % / CC1/2: 0.996 / Rmerge(I) obs: 0.146 / Rpim(I) all: 0.061 / Rrim(I) all: 0.158 / Χ2: 0.98 / Net I/σ(I): 11.2 / Num. measured all: 728923
Reflection shellResolution: 2.81→2.96 Å / % possible obs: 100 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.964 / Num. measured all: 106147 / Num. unique obs: 15631 / CC1/2: 0.791 / Rpim(I) all: 0.399 / Rrim(I) all: 1.044 / Χ2: 0.91 / Net I/σ(I) obs: 2.4

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
SCALEPACKdata scaling
PHASER2.6.0phasing
PDB_EXTRACT3.24data extraction
HKL-3000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.81→78.122 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.71 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2577 1999 1.85 %
Rwork0.1878 --
obs0.1891 108329 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.81→78.122 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms31320 0 360 21 31701
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.04232677
X-RAY DIFFRACTIONf_angle_d2.11644458
X-RAY DIFFRACTIONf_dihedral_angle_d15.74719204
X-RAY DIFFRACTIONf_chiral_restr0.1494703
X-RAY DIFFRACTIONf_plane_restr0.0155758
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8102-2.88050.36111410.27217540X-RAY DIFFRACTION100
2.8805-2.95840.34541410.25937473X-RAY DIFFRACTION100
2.9584-3.04540.32331410.2557503X-RAY DIFFRACTION100
3.0454-3.14370.36931420.24887531X-RAY DIFFRACTION100
3.1437-3.25610.35031410.23457534X-RAY DIFFRACTION100
3.2561-3.38650.29241420.22167546X-RAY DIFFRACTION100
3.3865-3.54060.33891420.21817520X-RAY DIFFRACTION100
3.5406-3.72730.24151420.19497557X-RAY DIFFRACTION100
3.7273-3.96080.26561420.18377592X-RAY DIFFRACTION100
3.9608-4.26660.22911420.16317571X-RAY DIFFRACTION100
4.2666-4.69590.22251440.14187637X-RAY DIFFRACTION100
4.6959-5.37530.20031440.14917667X-RAY DIFFRACTION100
5.3753-6.77170.24621460.18357718X-RAY DIFFRACTION100
6.7717-78.1220.20751490.16877941X-RAY DIFFRACTION99

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