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- PDB-8xgt: Crystal structure of human secretory glutaminyl cyclase in comple... -

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Basic information

Entry
Database: PDB / ID: 8xgt
TitleCrystal structure of human secretory glutaminyl cyclase in complex with (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-hydroxyindolin-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 / extracellular region / zinc ion binding
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: 2.813 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

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)454,80136
Polymers450,68912
Non-polymers4,11224
Water543
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


Theoretical massNumber of molelcules
Total (without water)454,80136
Polymers450,68912
Non-polymers4,11224
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1/2,-y,z+1/21
Buried area26940 Å2
ΔGint-119 kcal/mol
Surface area137180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.962, 217.386, 242.375
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-A1D48 / (3~{Z})-3-(1~{H}-benzimidazol-5-ylmethylidene)-4-oxidanyl-1~{H}-indol-2-one / (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-hydroxyindolin-2-one


Mass: 277.277 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C16H11N3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 2.45 Å3/Da / Density % sol: 49.88 %
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→161.83 Å / Num. obs: 107900 / % possible obs: 99.3 % / Redundancy: 6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.114 / Rpim(I) all: 0.051 / Rrim(I) all: 0.125 / Χ2: 0.98 / Net I/σ(I): 13.5 / Num. measured all: 646754
Reflection shellResolution: 2.81→2.96 Å / % possible obs: 100 % / Redundancy: 6 % / Rmerge(I) obs: 0.883 / Num. measured all: 94452 / Num. unique obs: 15619 / CC1/2: 0.815 / Rpim(I) all: 0.391 / Rrim(I) all: 0.967 / Χ2: 0.88 / 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: 2.813→54.857 Å / SU ML: 0.4 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.282 1998 1.86 %
Rwork0.194 --
obs0.1956 107692 99.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.813→54.857 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms31320 0 264 3 31587
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.03832592
X-RAY DIFFRACTIONf_angle_d1.94644316
X-RAY DIFFRACTIONf_dihedral_angle_d15.41219164
X-RAY DIFFRACTIONf_chiral_restr0.1294692
X-RAY DIFFRACTIONf_plane_restr0.0135748
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.813-2.8830.39811420.2727522X-RAY DIFFRACTION100
2.883-2.9610.36041410.2657468X-RAY DIFFRACTION100
2.961-3.04810.39741430.25137529X-RAY DIFFRACTION100
3.0481-3.14650.3371420.25357522X-RAY DIFFRACTION100
3.1465-3.25890.33181420.24677541X-RAY DIFFRACTION100
3.2589-3.38940.36641420.23127566X-RAY DIFFRACTION100
3.3894-3.54360.34421430.22217520X-RAY DIFFRACTION100
3.5436-3.73040.33821290.21346889X-RAY DIFFRACTION91
3.7304-3.96410.2791440.20067608X-RAY DIFFRACTION100
3.9641-4.270.26451440.17387581X-RAY DIFFRACTION100
4.27-4.69950.21131440.14927639X-RAY DIFFRACTION100
4.6995-5.37910.2571450.15337651X-RAY DIFFRACTION100
5.3791-6.77510.2611460.18737727X-RAY DIFFRACTION100
6.7751-54.8570.22421510.1717931X-RAY DIFFRACTION99

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