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

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Basic information

Entry
Database: PDB / ID: 8xga
TitleCrystal structure of human Golgi resident glutaminyl cyclase in complex with (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-((tetrahydro-2H-pyran-4-yl)oxy)indolin-2-one
ComponentsGlutaminyl-peptide cyclotransferase-like protein
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 / Golgi membrane / Golgi apparatus / zinc ion binding / membrane
Similarity search - Function
M28 Zn-Peptidase Glutaminyl Cyclase / Glutaminyl-peptide cyclotransferase-like / Peptidase M28 / Peptidase family M28
Similarity search - Domain/homology
: / Glutaminyl-peptide cyclotransferase-like protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.537 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 15, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)389,57833
Polymers384,88311
Non-polymers4,69522
Water724
1
A: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
H: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
9
I: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
10
J: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
11
K: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4163
Polymers34,9891
Non-polymers4272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)125.689, 108.008, 159.816
Angle α, β, γ (deg.)90.00, 104.59, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Glutaminyl-peptide cyclotransferase-like protein / Golgi-resident glutaminyl-peptide cyclotransferase / isoQC / gQC


Mass: 34989.387 Da / Num. of mol.: 11
Source method: isolated from a genetically manipulated source
Details: Homo sapiens / Source: (gene. exp.) Homo sapiens (human) / Gene: QPCTL / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9NXS2, glutaminyl-peptide cyclotransferase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-A1D47 / (3~{Z})-3-(1~{H}-benzimidazol-5-ylmethylidene)-4-(oxan-4-yloxy)-1~{H}-indol-2-one / (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-((tetrahydro-2H-pyran-4-yl)oxy)indolin-2-one


Mass: 361.394 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C21H19N3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 2.73 Å3/Da / Density % sol: 54.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 25%-28% PEG 3350, 0.1M HEPES, pH 7.5

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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: 3.537→154.66 Å / Num. obs: 48967 / % possible obs: 96.3 % / Redundancy: 3.4 % / CC1/2: 0.988 / Rmerge(I) obs: 0.135 / Rpim(I) all: 0.085 / Rrim(I) all: 0.16 / Χ2: 0.44 / Net I/σ(I): 5.4
Reflection shellResolution: 3.54→3.73 Å / % possible obs: 85.2 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.468 / Num. measured all: 20869 / Num. unique obs: 6301 / CC1/2: 0.83 / Rpim(I) all: 0.299 / Rrim(I) all: 0.557 / Χ2: 0.43 / Net I/σ(I) obs: 2.1

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHASER2.6.0phasing
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.24data extraction
HKL-3000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.537→74.279 Å / SU ML: 0.52 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 29.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2804 1998 4.09 %
Rwork0.199 --
obs0.2024 48871 95.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.537→74.279 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms27214 0 308 4 27526
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0128437
X-RAY DIFFRACTIONf_angle_d1.05838874
X-RAY DIFFRACTIONf_dihedral_angle_d16.37116951
X-RAY DIFFRACTIONf_chiral_restr0.0474356
X-RAY DIFFRACTIONf_plane_restr0.0095005
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.537-3.6250.38391470.24823446X-RAY DIFFRACTION99
3.625-3.72310.3411040.24962442X-RAY DIFFRACTION70
3.7231-3.83260.30441460.24273415X-RAY DIFFRACTION99
3.8326-3.95630.26031260.21842976X-RAY DIFFRACTION86
3.9563-4.09770.32661470.22573438X-RAY DIFFRACTION99
4.0977-4.26170.28611450.20413425X-RAY DIFFRACTION99
4.2617-4.45570.29311490.1893468X-RAY DIFFRACTION99
4.4557-4.69060.24621470.18633468X-RAY DIFFRACTION99
4.6906-4.98440.24551470.18023435X-RAY DIFFRACTION99
4.9844-5.36910.27841470.1943471X-RAY DIFFRACTION99
5.3691-5.90920.28711470.20743440X-RAY DIFFRACTION99
5.9092-6.76380.2961480.21083477X-RAY DIFFRACTION99
6.7638-8.51970.281480.18813487X-RAY DIFFRACTION99
8-74.2790.23331500.15743485X-RAY DIFFRACTION96

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