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

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Basic information

Entry
Database: PDB / ID: 8xfv
TitleCrystal structure of human Golgi resident glutaminyl cyclase in complex with (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-(piperidin-4-yloxy)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: 3.13 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 14, 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
Revision 1.2Oct 23, 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
X: Glutaminyl-peptide cyclotransferase-like protein
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)389,56733
Polymers384,88311
Non-polymers4,68422
Water181
1
X: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
B: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
C: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
D: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
E: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
F: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
G: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
9
H: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
10
I: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
11
J: Glutaminyl-peptide cyclotransferase-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4153
Polymers34,9891
Non-polymers4262
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)126.279, 109.126, 159.537
Angle α, β, γ (deg.)90.00, 104.73, 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
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-A1D46 / 3-(1~{H}-benzimidazol-5-ylmethylidene)-4-piperidin-4-yloxy-1~{H}-indol-2-one / (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-(piperidin-4-yloxy)indolin-2-one


Mass: 360.409 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C21H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.76 Å3/Da / Density % sol: 55.47 %
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: 3.13→154.29 Å / Num. obs: 70700 / % possible obs: 95.3 % / Redundancy: 3.4 % / CC1/2: 0.996 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.062 / Rrim(I) all: 0.115 / Χ2: 0.98 / Net I/σ(I): 11.2 / Num. measured all: 240337
Reflection shellResolution: 3.13→3.3 Å / % possible obs: 99.7 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.614 / Num. measured all: 38234 / Num. unique obs: 10747 / CC1/2: 0.842 / Rpim(I) all: 0.38 / Rrim(I) all: 0.724 / Χ2: 0.96 / Net I/σ(I) obs: 2.4

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
Aimlessdata scaling
PHASER2.6.0phasing
PDB_EXTRACT3.24data extraction
HKL-3000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.13→42.869 Å / SU ML: 0.51 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 32.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2837 1997 2.83 %
Rwork0.2046 --
obs0.2068 70558 95.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.13→42.869 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms27214 0 308 1 27523
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0228397
X-RAY DIFFRACTIONf_angle_d1.838842
X-RAY DIFFRACTIONf_dihedral_angle_d16.53216919
X-RAY DIFFRACTIONf_chiral_restr0.0774368
X-RAY DIFFRACTIONf_plane_restr0.0134999
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.13-3.20780.40571490.27435125X-RAY DIFFRACTION100
3.2078-3.29450.3481480.26225062X-RAY DIFFRACTION100
3.2945-3.39150.32061500.25395133X-RAY DIFFRACTION100
3.3915-3.50090.33741060.25533653X-RAY DIFFRACTION72
3.5009-3.62590.36451480.24435114X-RAY DIFFRACTION100
3.6259-3.7710.35531290.24354441X-RAY DIFFRACTION87
3.771-3.94250.3651230.23094198X-RAY DIFFRACTION82
3.9425-4.15020.27591470.21455066X-RAY DIFFRACTION99
4.1502-4.410.26351500.18495119X-RAY DIFFRACTION99
4.41-4.75010.25151490.17445111X-RAY DIFFRACTION99
4.7501-5.22740.27081490.17955122X-RAY DIFFRACTION99
5.2274-5.98210.2611490.20115128X-RAY DIFFRACTION99
5.9821-7.53010.26191490.20435123X-RAY DIFFRACTION99
7.5301-42.8690.21621510.16175166X-RAY DIFFRACTION98

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