Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity

Catherine E Fitzgerald; Sangita B Patel; Joseph W Becker; Patricia M Cameron; Dennis Zaller; Vasilis Bill Pikounis; Stephen J O'Keefe; Giovanna Scapin

doi:10.1038/nsb949

Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity

Nat Struct Biol. 2003 Sep;10(9):764-9. doi: 10.1038/nsb949. Epub 2003 Aug 3.

Authors

Catherine E Fitzgerald¹, Sangita B Patel, Joseph W Becker, Patricia M Cameron, Dennis Zaller, Vasilis Bill Pikounis, Stephen J O'Keefe, Giovanna Scapin

Affiliation

¹ Department of Immunology, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA.

PMID: 12897767
DOI: 10.1038/nsb949

Abstract

The quinazolinone and pyridol-pyrimidine classes of p38 MAP kinase inhibitors have a previously unseen degree of specificity for p38 over other MAP kinases. Comparison of the crystal structures of p38 bound to four different compounds shows that binding of the more specific molecules is characterized by a peptide flip between Met109 and Gly110. Gly110 is a residue specific to the alpha, beta and gamma isoforms of p38. The delta isoform and the other MAP kinases have bulkier residues in this position. These residues would likely make the peptide flip energetically unfavorable, thus explaining the selectivity of binding. To test this hypothesis, we constructed G110A and G110D mutants of p38 and measured the potency of several compounds against them. The results confirm that the selectivity of quinazolinones and pyridol-pyrimidines results from the presence of a glycine in position 110. This unique mode of binding may be exploited in the design of new p38 inhibitors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Sequence
Animals
Cloning, Molecular
Enzyme Inhibitors / pharmacology*
Glycine / chemistry
Imidazoles / pharmacology*
Inhibitory Concentration 50
Kinetics
Mice
Mitogen-Activated Protein Kinase 14
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Mitogen-Activated Protein Kinases / chemistry*
Models, Chemical
Models, Molecular
Molecular Sequence Data
Mutation
Peptides / chemistry
Protein Binding
Protein Isoforms
Protein Structure, Tertiary
Pyridazines / pharmacology*
Pyridines / pharmacology*
Pyrimidines / pharmacology*
Quinazolines / pharmacology*
Sequence Homology, Amino Acid

Substances

4-(4-fluorophenyl)-1-(4-piperidinyl)-5-(4-pyridyl)-imidazole
Enzyme Inhibitors
Imidazoles
Peptides
Protein Isoforms
Pyridazines
Pyridines
Pyrimidines
Quinazolines
Mitogen-Activated Protein Kinase 14
Mitogen-Activated Protein Kinases
SB 203580
Glycine
VX-745

Associated data

PDB/1OUK
PDB/1OUY
PDB/1OVE