Nature Structural Biology10, 764 - 769 (2003)
Published online: 3 August 2003; | doi:10.1038/nsb949
Structural basis for p38 MAP kinase quinazolinone and
pyridol-pyrimidine inhibitor specificity
Catherine E Fitzgerald1, Sangita B Patel2, Joseph W Becker2, Patricia M Cameron1, Dennis Zaller1, Vasilis Bill Pikounis3, Stephen J O'Keefe1
& Giovanna Scapin2
1
Departments of Immunology and Rheumatology, Merck
Research Laboratories, PO Box 2000, Rahway, New
Jersey 07065, USA.
2
Department of Medicinal Chemistry, Merck Research
Laboratories, PO Box 2000, Rahway, New Jersey
07065, USA.
3
Department of Biometrics Research, Merck Research
Laboratories, PO Box 2000, Rahway, New Jersey
07065, USA.
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 , and isoforms of p38. The
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.
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MAP kinase quinazolinone and
pyridol-pyrimidine inhibitor specificity
, 
and 
isoforms of p38. The 
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.
