4ZY6

Crystal structure of P21-activated kinase 1 in complex with an inhibitor compound 29


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.

Crawford, J.J.Lee, W.Aliagas, I.Mathieu, S.Hoeflich, K.P.Zhou, W.Wang, W.Rouge, L.Murray, L.La, H.Liu, N.Fan, P.W.Cheong, J.Heise, C.E.Ramaswamy, S.Mintzer, R.Liu, Y.Chao, Q.Rudolph, J.

(2015) J Med Chem 58: 5121-5136

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00572
  • Primary Citation of Related Structures:  
    4ZY4, 4ZY5, 4ZY6, 5BMS

  • PubMed Abstract: 

    The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.


  • Organizational Affiliation

    #Shanghai Chempartner Inc., 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, People's Republic of China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase PAK 1
A, B
301Homo sapiensMutation(s): 1 
Gene Names: PAK1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q13153 (Homo sapiens)
Explore Q13153 
Go to UniProtKB:  Q13153
PHAROS:  Q13153
GTEx:  ENSG00000149269 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13153
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4T6
Query on 4T6

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
N~2~-[(7-chloro-1H-benzimidazol-6-yl)methyl]-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine
C18 H17 Cl N8
DYLHVDVCWIEYSA-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
4T6 Binding MOAD:  4ZY6 Ki: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.634α = 90
b = 82.241β = 106.11
c = 66.137γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-01
    Type: Initial release
  • Version 1.1: 2015-07-15
    Changes: Database references
  • Version 1.2: 2015-12-16
    Changes: Refinement description