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- PDB-9q66: Human prolyl endopeptidase (PREP) - complex with JP-4-1-7 -

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Basic information

Entry
Database: PDB / ID: 9q66
TitleHuman prolyl endopeptidase (PREP) - complex with JP-4-1-7
ComponentsProlyl endopeptidase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / inhibitor-bound / peptide cleavage / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


prolyl oligopeptidase / oligopeptidase activity / angiotensin maturation / metallocarboxypeptidase activity / serine-type peptidase activity / serine-type endopeptidase activity / proteolysis / extracellular region / nucleus / membrane ...prolyl oligopeptidase / oligopeptidase activity / angiotensin maturation / metallocarboxypeptidase activity / serine-type peptidase activity / serine-type endopeptidase activity / proteolysis / extracellular region / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
: / Peptidase S9A, prolyl oligopeptidase / Peptidase S9A, N-terminal domain / Prolyl oligopeptidase, N-terminal beta-propeller domain / Prolyl endopeptidase family serine active site. / Peptidase S9, serine active site / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
: / THIOCYANATE ION / Prolyl endopeptidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.01 Å
AuthorsFucci, I.J. / Thakur, K. / Pandian, J. / Yoo, E. / Monteiro, D.C.F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2026
Title: Structure-Guided Optimization of 4-Chloro-Pyrazolopyridine Analogs for Covalent PREP Inhibition.
Authors: Thakur, K. / Fucci, I. / Pandian, J. / Suazo, K.F. / Monteiro, D.C.F. / Yoo, E.
History
DepositionAug 21, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Prolyl endopeptidase
B: Prolyl endopeptidase
C: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)244,99919
Polymers242,5543
Non-polymers2,44516
Water13,313739
1
A: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,9248
Polymers80,8511
Non-polymers1,0737
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,5846
Polymers80,8511
Non-polymers7325
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,4925
Polymers80,8511
Non-polymers6404
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)105.853, 67.294, 158.019
Angle α, β, γ (deg.)90, 99.109, 90
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 3 molecules ABC

#1: Protein Prolyl endopeptidase / PE / Post-proline cleaving enzyme


Mass: 80851.367 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PREP, PEP / Production host: Escherichia coli (E. coli) / References: UniProt: P48147, prolyl oligopeptidase

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Non-polymers , 5 types, 755 molecules

#2: Chemical ChemComp-A1CQP / 4-chloro-1-(cyclohexylmethyl)-3-methyl-N-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide


Mass: 431.959 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H30ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-B3P / 2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL


Mass: 282.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H26N2O6 / Comment: pH buffer*YM
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: CNS
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 739 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.29 Å3/Da / Density % sol: 46.31 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 25-30% PEG 3350, 200 mM KSCN and 100 mM bis-tris propane pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.919764 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 5, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.919764 Å / Relative weight: 1
ReflectionResolution: 2.01→44 Å / Num. obs: 106903 / % possible obs: 93.4 % / Redundancy: 7.1 % / Biso Wilson estimate: 24.4 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.273 / Rpim(I) all: 0.11 / Rrim(I) all: 0.294 / Net I/σ(I): 5.9
Reflection shellResolution: 2.01→2.22 Å / Redundancy: 7.5 % / Rmerge(I) obs: 1.53 / Num. unique obs: 5345 / CC1/2: 0.33 / Rpim(I) all: 0.596 / Rrim(I) all: 1.643 / % possible all: 54.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0430 (refmacat 0.4.105)refinement
autoPROCdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.01→44 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.885 / SU B: 17.831 / SU ML: 0.231 / Cross valid method: FREE R-VALUE / ESU R: 0.325 / ESU R Free: 0.254
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.266 5347 5.002 %
Rwork0.1845 101556 -
all0.189 --
obs-106903 73.378 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 34.517 Å2
Baniso -1Baniso -2Baniso -3
1-0.227 Å20 Å2-0.617 Å2
2---0.232 Å20 Å2
3---0.193 Å2
Refinement stepCycle: LAST / Resolution: 2.01→44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17019 0 157 739 17915
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.01217658
X-RAY DIFFRACTIONr_bond_other_d0.0010.01616180
X-RAY DIFFRACTIONr_angle_refined_deg2.8331.8223932
X-RAY DIFFRACTIONr_angle_other_deg0.921.76337388
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.40952124
X-RAY DIFFRACTIONr_dihedral_angle_2_deg24.2636.87596
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg7.44153
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.767102913
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.98510852
X-RAY DIFFRACTIONr_chiral_restr0.120.22521
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.0220718
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024122
X-RAY DIFFRACTIONr_nbd_refined0.2360.24166
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2250.216934
X-RAY DIFFRACTIONr_nbtor_refined0.2070.28607
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.1070.29818
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1960.2979
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1010.225
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2630.237
X-RAY DIFFRACTIONr_nbd_other0.2590.2136
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2660.214
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.090.21
X-RAY DIFFRACTIONr_mcbond_it1.9851.5498494
X-RAY DIFFRACTIONr_mcbond_other1.9661.5488491
X-RAY DIFFRACTIONr_mcangle_it3.0562.77210605
X-RAY DIFFRACTIONr_mcangle_other3.0562.77210606
X-RAY DIFFRACTIONr_scbond_it2.3541.7579164
X-RAY DIFFRACTIONr_scbond_other2.3521.7579163
X-RAY DIFFRACTIONr_scangle_it3.6233.12913324
X-RAY DIFFRACTIONr_scangle_other3.6133.12813323
X-RAY DIFFRACTIONr_lrange_it5.39916.04920644
X-RAY DIFFRACTIONr_lrange_other5.38815.99920539
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.014-2.0660.550.29799X-RAY DIFFRACTION0.9726
2.066-2.1230.384240.314602X-RAY DIFFRACTION5.9962
2.123-2.1840.3481170.3142269X-RAY DIFFRACTION23.6519
2.184-2.2510.3482000.3014230X-RAY DIFFRACTION44.7113
2.251-2.3250.353030.2936016X-RAY DIFFRACTION66.1745
2.325-2.4060.3574100.287270X-RAY DIFFRACTION83.0989
2.406-2.4970.3274280.2638135X-RAY DIFFRACTION96.4519
2.497-2.5990.3284480.2428134X-RAY DIFFRACTION99.6864
2.599-2.7140.294310.2187808X-RAY DIFFRACTION100
2.714-2.8460.2893840.1987495X-RAY DIFFRACTION99.9873
2.846-2.9990.2693840.1957113X-RAY DIFFRACTION100
2.999-3.180.3013420.1876803X-RAY DIFFRACTION100
3.18-3.3980.2633510.1826345X-RAY DIFFRACTION100
3.398-3.6690.2393020.1675926X-RAY DIFFRACTION100
3.669-4.0160.2582780.155477X-RAY DIFFRACTION100
4.016-4.4850.2082570.1255014X-RAY DIFFRACTION100
4.485-5.170.1952250.1184391X-RAY DIFFRACTION100
5.17-6.3110.2492140.1363739X-RAY DIFFRACTION100
6.311-8.8350.221510.142946X-RAY DIFFRACTION100
8.835-440.174930.1511744X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.99060.3035-0.31920.9718-0.17190.85890.0191-0.04170.0250.055-0.013-0.1005-0.06060.0707-0.00610.01-0.0123-0.00080.0227-0.01080.0192-1.09740.659354.4474
21.2920.1672-0.28091.2023-0.18531.3298-0.0101-0.0538-0.05460.01640.0048-0.36140.1870.27250.00520.0550.05410.00080.1252-0.0350.136929.051-0.4736104.9144
31.2133-0.0929-0.27321.1854-0.36661.2813-0.0445-0.06350.08010.08970.0487-0.14070.07480.0191-0.00420.1481-0.010.020.1532-0.05090.101954.61224.195155.2068
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLAp4 - 807
2X-RAY DIFFRACTION2ALLBp4 - 804
3X-RAY DIFFRACTION3ALLCp4 - 804

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