4APP

Crystal Structure of the Human p21-Activated Kinase 4 in Complex with (S)-N-(5-(3-benzyl-1-methylpiperazine-4-carbonyl)-6,6-dimethyl-1,4,5, 6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-phenoxybenzamide

PDB DOI: https://doi.org/10.2210/pdb4APP/pdb

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

Deposited: 2012-04-04 Released: 2012-06-06
Deposition Author(s): Knighton, D.D., Deng, Y.L., Wang, C., Guo, C., McAlpine, I., Zhang, J., Kephart, S., Johnson, M.C., Li, H., Bouzida, D., Yang, A., Dong, L., Marakovits, J., Tikhe, J., Richardson, P., Guo, L.C., Kania, R., Edwards, M.P., Kraynov, E., Christensen, J., Piraino, J., Lee, J., Dagostino, E., Del-Carmen, C., Smeal, T., Murray, B.W.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.20 Å
R-Value Free: 0.229
R-Value Work: 0.188

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Discovery of Pyrroloaminopyrazoles as Novel Pak Inhibitors.

Guo, C., Mcalpine, I., Zhang, J., Knighton, D.D., Kephart, S., Johnson, M.C., Li, H., Bouzida, D., Yang, A., Dong, L., Marakovits, J., Tikhe, J., Richardson, P., Guo, L.C., Kania, R., Edwards, M.P., Kraynov, E., Christensen, J., Piraino, J., Lee, J., Dagostino, E., Del-Carmen, C., Deng, Y.L., Smeal, T., Murray, B.W.

(2012) J Med Chem 55: 4728

PubMed: 22554206 Search on PubMed
DOI: https://doi.org/10.1021/jm300204j
Primary Citation of Related Structures:
4APP

PubMed Abstract:
The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.

Organizational Affiliation

Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States. alexguo01@gmail.com

Macromolecule Content

Total Structure Weight: 34.08 kDa
Atom Count: 2,542
Modelled Residue Count: 293
Deposited Residue Count: 296
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
SERINE/THREONINE-PROTEIN KINASE PAK 4	A	296	Homo sapiens	Mutation(s): 0 EC: 2.7.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for O96013 (Homo sapiens) Explore O96013 Go to UniProtKB: O96013
PHAROS: O96013 GTEx: ENSG00000130669
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O96013
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
N53 Query on N53 Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	N-[6,6-dimethyl-5-[(2S)-4-methyl-2-(phenylmethyl)piperazin-1-yl]carbonyl-2,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-phenoxy-benzamide C₃₃ H₃₆ N₆ O₃ VGRHRLOVUZTBHT-VWLOTQADSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
SEP Query on SEP	A	L-PEPTIDE LINKING	C₃ H₈ N O₆ P		SER

Binding Affinity Annotations
ID	Source	Binding Affinity
N53	BindingDB: 4APP	Ki: 64 (nM) from 1 assay(s)
	BindingDB: 4APP	EC50: 810 (nM) from 1 assay(s)
	PDBBind: 4APP	Ki: 64 (nM) from 1 assay(s)
	Binding MOAD: 4APP	Ki: 64 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.20 Å
R-Value Free: 0.229
R-Value Work: 0.188
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 51.424	α = 90
b = 64.995	β = 90
c = 85.829	γ = 90

Software Package:

Software Name	Purpose
CNX	refinement
HKL-2000	data reduction
SCALEPACK	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-06-06

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2012-06-06
Type: Initial release
Version 1.1: 2019-05-08
Changes: Data collection, Derived calculations, Experimental preparation, Other