1OUY

The structure of p38 alpha in complex with a dihydropyrido-pyrimidine inhibitor

Summary for 1OUY

• Entry DOI: 10.2210/pdb1ouy/pdb
• Related: 1M7Q 1OUK 1OVE
• Descriptor: Mitogen-activated protein kinase 14, 1-(2,6-DICHLOROPHENYL)-6-[(2,4-DIFLUOROPHENYL)SULFANYL]-7-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)-3,4-DIHYDROPYRIDO[3,2-D]PYRIMIDIN-2(1H)-ONE (3 entities in total)
• Functional Keywords: map kinase, hydrophobic pocket, kinase domain, atp binding domain, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 42518.33

Authors

Fitzgerald, C.E.,Patel, S.B.,Becker, J.W.,Cameron, P.M.,Zaller, D.,Pikounis, V.B.,O'Keefe, S.J.,Scapin, G. (deposition date: 2003-03-25, release date: 2003-09-02, Last modification date: 2023-08-16)

Primary citation

Fitzgerald, C.E.,Patel, S.B.,Becker, J.W.,Cameron, P.M.,Zaller, D.,Pikounis, V.B.,O'Keefe, S.J.,Scapin, G.
Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity
Nat.Struct.Biol., 10:764-769, 2003

PubMed 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.

PubMed: 12897767
DOI: 10.1038/nsb949

Experimental method

X-RAY DIFFRACTION (2.5 Å)