PDBsum entry 5kbq

Transferase

PDB id: 5kbq

Contents

Protein chains

289 a.a.

273 a.a.

Ligands

IPV

Waters ×49

PDB id:

5kbq

Name:

Transferase

Title:

Pak1 in complex with bis-anilino pyrimidine inhibitor

Structure:

Serine/threonine-protein kinase pak 1. Chain: a, b. Synonym: alpha-pak,p21-activated kinase 1,pak-1,p65-pak. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pak1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.58Å R-factor: 0.178 R-free: 0.230

Authors:

A.Ferguson

Key ref:

W.McCoull et al. (2016). Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors. ACS Med Chem Lett, 7, 1118-1123. PubMed id: 27994749

Date:

03-Jun-16 Release date: 28-Sep-16

Protein chain

Q13153  (PAK1_HUMAN) -  Serine/threonine-protein kinase PAK 1 from Homo sapiens

Seq: 545 a.a.

Struc: 289 a.a.*

Protein chain

Q13153  (PAK1_HUMAN) -  Serine/threonine-protein kinase PAK 1 from Homo sapiens

Seq: 545 a.a.

Struc: 273 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

ACS Med Chem Lett 7:1118-1123 (2016)

PubMed id: 27994749

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors.

W.McCoull, E.J.Hennessy, K.Blades, C.Chuaqui, J.E.Dowling, A.D.Ferguson, F.W.Goldberg, N.Howe, C.R.Jones, P.D.Kemmitt, G.Lamont, J.G.Varnes, R.A.Ward, B.Yang.

ABSTRACT

Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, givingin vitroprobe compoundAZ13705339(18). Reduction of lipophilicity to lower clearance affordedAZ13711265(14) as anin vivoprobe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.