PDBsum entry 4zlo

Transferase/transferase inhibitor

PDB id: 4zlo

Contents

Protein chains

278 a.a.

264 a.a.

Ligands

4PV

GOL

Waters ×121

PDB id:

4zlo

Name:

Transferase/transferase inhibitor

Title:

Serine/threonine-protein kinase pak1 complexed with a dibenzodiazepine: identification of an allosteric site on pak1

Structure:

Serine/threonine-protein kinase pak 1. Chain: a, b. Synonym: alpha-pak,p21-activated kinase 1,pak-1,p65-pak. Engineered: yes. Other_details: residue 177 is phosphorylated threonine

Source:

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

Resolution:

2.50Å R-factor: 0.196 R-free: 0.222

Authors:

C.R.Bellamacina,D.E.Bussiere

Key ref:

A.S.Karpov et al. (2015). Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor. Acs Med Chem Lett, 6, 776-781. PubMed id: 26191365 DOI: 10.1021/acsmedchemlett.5b00102

Date:

01-May-15 Release date: 05-Aug-15

Protein chain

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

Seq: 545 a.a.

Struc: 278 a.a.*

Protein chain

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

Seq: 545 a.a.

Struc: 264 a.a.*

* PDB and UniProt seqs differ at 2 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

DOI no: 10.1021/acsmedchemlett.5b00102

Acs Med Chem Lett 6:776-781 (2015)

PubMed id: 26191365

Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.

A.S.Karpov, P.Amiri, C.Bellamacina, M.H.Bellance, W.Breitenstein, D.Daniel, R.Denay, D.Fabbro, C.Fernandez, I.Galuba, S.Guerro-Lagasse, S.Gutmann, L.Hinh, W.Jahnke, J.Klopp, A.Lai, M.K.Lindvall, S.Ma, H.Möbitz, S.Pecchi, G.Rummel, K.Shoemaker, J.Trappe, C.Voliva, S.W.Cowan-Jacob, A.L.Marzinzik.

ABSTRACT

The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.