1UK1

Crystal structure of human poly(ADP-ribose) polymerase complexed with a potent inhibitor

PDB DOI: https://doi.org/10.2210/pdb1UK1/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2003-08-14 Released: 2004-09-14
Deposition Author(s): Kinoshita, T.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.00 Å
R-Value Free: 0.274
R-Value Work: 0.242
R-Value Observed: 0.257

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Rational approaches to discovery of orally active and brain-penetrable quinazolinone inhibitors of poly(ADP-ribose)polymerase

Hattori, K., Kido, Y., Yamamoto, H., Ishida, J., Kamijo, K., Murano, K., Ohkubo, M., Kinoshita, T., Iwashita, A., Mihara, K., Yamazaki, S., Matsuoka, N., Teramura, Y., Miyake, H.

(2004) J Med Chem 47: 4151-4154

PubMed: 15293985 Search on PubMed
DOI: https://doi.org/10.1021/jm0499256
Primary Citation of Related Structures:
1UK1

PubMed Abstract:
A novel class of quinazolinone derivatives as potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors has been discovered. Key to success was application of a rational discovery strategy involving structure-based design, combinatorial chemistry, and classical SAR for improvement of potency and bioavailability. The new inhibitors were shown to bind to the nicotinamide-ribose binding site (NI site) and the adenosine-ribose binding site (AD site) of NAD+.

Organizational Affiliation

Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. kouji_hattori@ po.fujisawa.co.jp

Macromolecule Content

Total Structure Weight: 79.18 kDa
Atom Count: 5,757
Modelled Residue Count: 700
Deposited Residue Count: 700
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Poly [ADP-ribose] polymerase-1	A, B	350	Homo sapiens	Mutation(s): 0 EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for P09874 (Homo sapiens) Explore P09874 Go to UniProtKB: P09874
PHAROS: P09874 GTEx: ENSG00000143799
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P09874
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FRQ Query on FRQ Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth B]	C [auth A], D [auth B]	5-FLUORO-1-[4-(4-PHENYL-3,6-DIHYDROPYRIDIN-1(2H)-YL)BUTYL]QUINAZOLINE-2,4(1H,3H)-DIONE C₂₃ H₂₄ F N₃ O₂ PNPFDRCIGCUCMN-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
FRQ	PDBBind: 1UK1	IC50: 60 (nM) from 1 assay(s)
FRQ	BindingDB: 1UK1	IC50: 60 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 3.00 Å
R-Value Free: 0.274
R-Value Work: 0.242
R-Value Observed: 0.257
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 179.96	α = 90
b = 53.27	β = 113.8
c = 91.47	γ = 90

Software Package:

Software Name	Purpose
DENZO	data reduction
SCALEPACK	data scaling
AMoRE	phasing
CNX	refinement

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2004-09-14

Deposition Author(s):

Kinoshita, T.

Revision History (Full details and data files)

Version 1.0: 2004-09-14
Type: Initial release
Version 1.1: 2008-04-27
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Version format compliance
Version 1.3: 2023-12-27
Changes: Data collection, Database references, Derived calculations