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- PDB-9q6x: Human prolyl endopeptidase (PREP) - complex with KT-2-186 -

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Basic information

Entry
Database: PDB / ID: 9q6x
TitleHuman prolyl endopeptidase (PREP) - complex with KT-2-186
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
: / DI(HYDROXYETHYL)ETHER / THIOCYANATE ION / Prolyl endopeptidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 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 22, 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
C: Prolyl endopeptidase
A: Prolyl endopeptidase
B: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)249,34868
Polymers242,5543
Non-polymers6,79465
Water28,2661569
1
C: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,02035
Polymers80,8511
Non-polymers3,16834
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,93520
Polymers80,8511
Non-polymers2,08419
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
B: Prolyl endopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,39413
Polymers80,8511
Non-polymers1,54212
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.736, 66.350, 156.296
Angle α, β, γ (deg.)90.00, 101.87, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 3 molecules CAB

#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 , 8 types, 1634 molecules

#2: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: CNS
#3: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical...
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 27 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-A1CQ1 / 4-chloro-3-methyl-N-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1-[2-(pyridin-3-yl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide


Mass: 426.899 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H23ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#7: 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.: 2 / Source method: obtained synthetically / Formula: C11H26N2O6 / Comment: pH buffer*YM
#8: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1569 / 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: 2.17 Å3/Da / Density % sol: 43.32 %
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: 0.919901 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: May 23, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.919901 Å / Relative weight: 1
ReflectionResolution: 1.66→34.6 Å / Num. obs: 182439 / % possible obs: 94.5 % / Redundancy: 7.1 % / Biso Wilson estimate: 13.9 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.232 / Rpim(I) all: 0.093 / Rrim(I) all: 0.251 / Net I/σ(I): 6
Reflection shellResolution: 1.66→1.84 Å / Redundancy: 6.9 % / Rmerge(I) obs: 1.437 / Num. unique obs: 9122 / CC1/2: 0.43 / Rpim(I) all: 0.591 / Rrim(I) all: 1.556 / % possible all: 56.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0430refinement
autoPROCdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.66→34.6 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.937 / SU B: 6.767 / SU ML: 0.106 / Cross valid method: THROUGHOUT / ESU R: 0.131 / ESU R Free: 0.132 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.21423 9026 4.9 %RANDOM
Rwork0.15885 ---
obs0.16159 173412 74.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.938 Å2
Baniso -1Baniso -2Baniso -3
1--0.17 Å20 Å2-0.08 Å2
2--0.21 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 1.66→34.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17019 0 429 1569 19017
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.01217936
X-RAY DIFFRACTIONr_bond_other_d0.0010.01616449
X-RAY DIFFRACTIONr_angle_refined_deg2.2671.81824227
X-RAY DIFFRACTIONr_angle_other_deg0.7551.75838052
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.25852142
X-RAY DIFFRACTIONr_dihedral_angle_2_deg12.959588
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.245102929
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1080.22557
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0220810
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024138
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.431.1668522
X-RAY DIFFRACTIONr_mcbond_other1.4261.1658519
X-RAY DIFFRACTIONr_mcangle_it2.0492.0810632
X-RAY DIFFRACTIONr_mcangle_other2.0492.0810633
X-RAY DIFFRACTIONr_scbond_it2.7871.499414
X-RAY DIFFRACTIONr_scbond_other2.7871.4919415
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.1332.57113584
X-RAY DIFFRACTIONr_long_range_B_refined5.91513.5820386
X-RAY DIFFRACTIONr_long_range_B_other5.86113.2320081
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.66→1.702 Å
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.253 83 -
obs--0.46 %
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)
10.32120.0273-0.13470.5817-0.19110.63530.0021-0.0360.02280.01880.0052-0.04150.00360.0437-0.00730.01190.0017-0.00610.0066-0.00520.008839.83091.630626.9077
20.64570.1064-0.21610.4393-0.02250.5618-0.02990.0006-0.02310.03440.0155-0.04920.04830.02990.01450.0180.0085-0.00980.0046-0.00460.01161.9816.781875.8717
30.9501-0.374-0.35210.64070.19220.5060.04520.01180.142-0.0636-0.0022-0.0104-0.0388-0.0423-0.0430.046-0.00310.00040.01780.00610.035991.638136.348123.1223
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1C4 - 833
2X-RAY DIFFRACTION2A4 - 818
3X-RAY DIFFRACTION3B4 - 813

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