Structural basis of inhibitor selectivity in MAP kinases

Zhulun Wang, Bertram J. Canagarajah, Jeffrey C. Boehm, Skouki Kassisà, Melanie H. Cobb, Peter R. Young, Sherin Abdel-Meguid, Jerry L. Adams, Elizabeth J. Goldsmith

Research output: Contribution to journalArticlepeer-review

414 Scopus citations


Background: The mitogen-activated protein (MAP) kinases are important signaling molecules that participate in diverse cellular events and are potential targets for intervention in inflammation, cancer, and other diseases. The MAP kinase p38 is responsive to environmental stresses and is involved in the production of cytokines during inflammation. In contrast, the activation of the MAP kinase ERK2 (extracellular-signal-regulated kinase 2) leads to cellular differentiation or proliferation. The anti-inflammatory agent pyridinylimidazole and its analogs (SB [SmithKline Beecham] compounds) are highly potent and selective inhibitors of p38, but not of the closely related ERK2, or other serine/threonine kinases. Although these compounds are known to bind to the ATP-binding site, the origin of the inhibitory specificity toward p38 is not clear. Results: We report the structural basis for the exceptional selectivity of these SB compounds for p38 over ERK2, as determined by comparative crystallography. In addition, structural data on the origin of olomoucine (a better inhibitor of ERK2) selectivity are presented. The crystal structures of four SB compounds in complex with p38 and of one SB compound and olomoucine in complex with ERK2 are presented here. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low-activity form of p38. The relatively closed domain structure of ERK2 is able to accommodate the smaller olomoucine. Conclusions: The unique kinase-inhibitor interactions observed in these complexes originate from amino-acid replacements in the active site and replacements distant from the active site that affect the size of the domain interface. This structural information should facilitate the design of better MAP-kinase inhibitors for the treatment of inflammation and other diseases.

Original languageEnglish (US)
Pages (from-to)1117-1128
Number of pages12
Issue number9
StatePublished - Sep 15 1998


  • ERK2
  • Inhibitor
  • MAP kinase
  • Olomoucine
  • p38

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


Dive into the research topics of 'Structural basis of inhibitor selectivity in MAP kinases'. Together they form a unique fingerprint.

Cite this