PDBsum entry 1wbv

Transferase

PDB id: 1wbv

Contents

Protein chain

352 a.a. *

Ligands

LI3

GOL ×3

DMS

Waters ×569

* Residue conservation analysis

PDB id:

1wbv

Name:

Transferase

Title:

Identification of novel p38 alpha map kinase inhibitors using fragment-based lead generation.

Structure:

Mitogen-activated protein kinase 14. Chain: a. Fragment: kinase domain, residues 1-360. Synonym: mitogen-activated protein kinase p38alpha, map kinase p38alpha, cytokine suppressive anti-inflammatory drug binding protein, csaid binding protein, csbp, max-interacting protein 2, map kinase mxi2, sapk2a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.00Å R-factor: 0.180 R-free: 0.233

Authors:

J.Tickle,A.Cleasby,L.A.Devine,H.Jhoti

Key ref:

A.L.Gill et al. (2005). Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation. J Med Chem, 48, 414-426. PubMed id: 15658855 DOI: 10.1021/jm049575n

Date:

05-Nov-04 Release date: 03-Nov-05

Protein chain

Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens

Seq: 360 a.a.

Struc: 352 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.24 - mitogen-activated 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/jm049575n

J Med Chem 48:414-426 (2005)

PubMed id: 15658855

Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.

A.L.Gill, M.Frederickson, A.Cleasby, S.J.Woodhead, M.G.Carr, A.J.Woodhead, M.T.Walker, M.S.Congreve, L.A.Devine, D.Tisi, M.O'Reilly, L.C.Seavers, D.J.Davis, J.Curry, R.Anthony, A.Padova, C.W.Murray, R.A.Carr, H.Jhoti.

ABSTRACT

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.