PDB-9q62: Human prolyl endopeptidase (PREP) - complex with KT-2-108

ID or keywords:

Entry

Database: PDB / ID: 9q62

Title

Human prolyl endopeptidase (PREP) - complex with KT-2-108

Components

Prolyl endopeptidase

Keywords

HYDROLASE/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 ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.83 Å

Authors

Fucci, I.J. / Thakur, K. / Pandian, J. / Yoo, E. / Monteiro, D.C.F.

Funding support

United States, 1items

Citation

Journal: 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

Deposition	Aug 21, 2025	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Jan 21, 2026	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	9q62.cif.gz	1.9 MB	Display	PDBx/mmCIF format
PDB format	pdb9q62.ent.gz		Display	PDB format
PDBx/mmJSON format	9q62.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/q6/9q62 ftp://data.pdbj.org/pub/pdb/validation_reports/q6/9q62	HTTPS FTP

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Related structure data

Related structure data	9q5gC 9q5xC 9q5yC 9q5zC 9q64C 9q65C 9q66C 9q6jC 9q6kC 9q6lC 9q6xC 9xykC 9xylC 9xzzC C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search
Experimental dataset #1	Data reference: 10.15785/SBGRID/1205 / Data set type: diffraction image data

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#202 - Oct 2016 Dipeptidyl Peptidase 4 similarity (4) #190 - Oct 2015 Two-component Systems similarity (1)

Deposited unit

A: Prolyl endopeptidase

B: Prolyl endopeptidase

C: Prolyl endopeptidase

hetero molecules

247 kDa, 3 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Prolyl endopeptidase

hetero molecules

defined by author
Evidence: gel filtration
82.7 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

B: Prolyl endopeptidase

hetero molecules

defined by author
82.2 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

3

C: Prolyl endopeptidase

hetero molecules

defined by author
81.9 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	106.189, 67.075, 157.164
Angle α, β, γ (deg.)	90, 99.198, 90
Int Tables number	4
Space group name H-M	P12₁1

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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 , 6 types, 1423 molecules

#2: Chemical	ChemComp-K / POTASSIUM ION Mass: 39.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: K
#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.: 4 / Source method: obtained synthetically / Formula: C₁₁H₂₆N₂O₆ / Comment: pH buffer*YM
#4: Chemical	ChemComp-A1CQQ / 4-chloro-3-methyl-N-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide Mass: 439.938 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C₂₃H₂₆ClN₅O₂ / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical	ChemComp-SCN / THIOCYANATE ION Mass: 58.082 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: CNS
#6: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C₃H₈O₃
#7: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 1389 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y
Has protein modification	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.28 Å³/Da / Density % sol: 46 %
Crystal grow	Temperature: 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

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.919764 Å
Detector	Type: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 5, 2025
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.919764 Å / Relative weight: 1
Reflection	Resolution: 1.83→43.9 Å / Num. obs: 144444 / % possible obs: 92.1 % / Redundancy: 6.8 % / B_iso Wilson estimate: 17.8 Å² / CC_1/2: 0.99 / R_merge(I) obs: 0.237 / R_pim(I) all: 0.097 / R_rim(I) all: 0.256 / Net I/σ(I): 6.6
Reflection shell	Resolution: 1.83→2 Å / R_merge(I) obs: 1.42 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 7222 / CC_1/2: 0.38 / R_pim(I) all: 0.589 / R_rim(I) all: 1.536

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0430 (refmacat 0.4.100)	refinement
autoPROC		data reduction
autoPROC		data scaling
MOLREP		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.83→43.9 Å / Cor.coef. F_o:F_c: 0.953 / Cor.coef. F_o:F_c free: 0.911 / SU B: 9.18 / SU ML: 0.143 / Cross valid method: FREE R-VALUE / ESU R: 0.194 / ESU R Free: 0.181
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2395	7173	4.966 %
R_work	0.1734	137270	-
all	0.177	-	-
obs	-	144443	74.441 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 25.592 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.133 Å²	0 Å²	-0.067 Å²
2-	-	-0.039 Å²	0 Å²
3-	-	-	-0.069 Å²

Refinement step

Cycle: LAST / Resolution: 1.83→43.9 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	17019	0	268	1389	18676

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.015	0.012	17734
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	16223
X-RAY DIFFRACTION	r_angle_refined_deg	2.57	1.818	24005
X-RAY DIFFRACTION	r_angle_other_deg	0.841	1.761	37498
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	8.141	5	2122
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	22.297	6.935	93
X-RAY DIFFRACTION	r_dihedral_angle_other_2_deg	3.116	5	3
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	16.122	10	2911
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	15.198	10	850
X-RAY DIFFRACTION	r_chiral_restr	0.115	0.2	2528
X-RAY DIFFRACTION	r_gen_planes_refined	0.013	0.02	20700
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	4124
X-RAY DIFFRACTION	r_nbd_refined	0.232	0.2	3881
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.214	0.2	16396
X-RAY DIFFRACTION	r_nbtor_refined	0.196	0.2	8535
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.101	0.2	9681
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.202	0.2	1419
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.146	0.2	9
X-RAY DIFFRACTION	r_metal_ion_refined	0.172	0.2	3
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.277	0.2	52
X-RAY DIFFRACTION	r_nbd_other	0.313	0.2	131
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.213	0.2	33
X-RAY DIFFRACTION	r_xyhbond_nbd_other	0.046	0.2	1
X-RAY DIFFRACTION	r_mcbond_it	1.641	1.239	8500
X-RAY DIFFRACTION	r_mcbond_other	1.597	1.236	8485
X-RAY DIFFRACTION	r_mcangle_it	2.495	2.213	10602
X-RAY DIFFRACTION	r_mcangle_other	2.495	2.213	10603
X-RAY DIFFRACTION	r_scbond_it	2.181	1.453	9234
X-RAY DIFFRACTION	r_scbond_other	2.181	1.453	9235
X-RAY DIFFRACTION	r_scangle_it	3.256	2.565	13401
X-RAY DIFFRACTION	r_scangle_other	3.256	2.565	13402
X-RAY DIFFRACTION	r_lrange_it	5.515	14.82	20773
X-RAY DIFFRACTION	r_lrange_other	5.515	14.821	20774

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
1.83-1.873	0.082	3	0.218	75	X-RAY DIFFRACTION	0.5469
1.873-1.924	0.314	12	0.293	403	X-RAY DIFFRACTION	2.9919
1.924-1.98	0.318	183	0.297	3621	X-RAY DIFFRACTION	28.1799
1.98-2.041	0.333	400	0.273	7670	X-RAY DIFFRACTION	61.271
2.041-2.108	0.309	516	0.28	9034	X-RAY DIFFRACTION	75.1909
2.108-2.181	0.297	572	0.242	11484	X-RAY DIFFRACTION	97.9048
2.181-2.263	0.289	532	0.231	10719	X-RAY DIFFRACTION	95.0013
2.263-2.356	0.268	575	0.203	10902	X-RAY DIFFRACTION	99.9913
2.356-2.46	0.263	580	0.19	10451	X-RAY DIFFRACTION	100
2.46-2.58	0.266	524	0.178	10010	X-RAY DIFFRACTION	99.962
2.58-2.719	0.255	417	0.169	8194	X-RAY DIFFRACTION	85.9896
2.719-2.883	0.25	473	0.163	8968	X-RAY DIFFRACTION	99.9894
2.883-3.081	0.249	424	0.16	8527	X-RAY DIFFRACTION	100
3.081-3.327	0.235	392	0.156	7933	X-RAY DIFFRACTION	100
3.327-3.642	0.224	322	0.152	6588	X-RAY DIFFRACTION	90.3268
3.642-4.068	0.203	294	0.13	5718	X-RAY DIFFRACTION	85.8735
4.068-4.691	0.186	336	0.112	5802	X-RAY DIFFRACTION	100
4.691-5.729	0.197	283	0.125	4978	X-RAY DIFFRACTION	100
5.729-8.034	0.173	202	0.151	3900	X-RAY DIFFRACTION	100
8.034-43.9	0.164	133	0.17	2293	X-RAY DIFFRACTION	100

Refinement TLS params.

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

ID	L11 (°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)
1	0.6671	0.1728	-0.209	0.6463	-0.0738	0.6459	0.0211	-0.0548	0.0194	0.0398	-0.0048	-0.0576	-0.0308	0.0682	-0.0163	0.0041	-0.0018	-0.0056	0.0136	-0.013	0.0275	-1.03	0.6495	54.062
2	0.8913	-0.0765	-0.2982	0.7577	-0.1149	0.9251	-0.0243	-0.0714	0.0284	0.0759	0.0386	-0.0411	0.0632	0.0242	-0.0143	0.076	-0.0001	-0.0179	0.0692	-0.0213	0.0604	-26.2881	3.8176	-0.7397
3	0.8753	0.0607	-0.2025	0.7049	-0.0069	0.9931	-0.0027	-0.0652	-0.017	0.0504	0.0283	-0.1667	0.1157	0.2056	-0.0256	0.049	0.0396	-0.0262	0.0861	-0.0241	0.0914	-51.904	-0.5774	-50.9274

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	ALL	Ap	4 - 710
2	X-RAY DIFFRACTION	2	ALL	Bp	4 - 710
3	X-RAY DIFFRACTION	3	ALL	Cp	4 - 710

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