title: Structural basis of inhibitor selectivity in MAP kinases.
abstract: 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.
authors.affiliation: Department of Biochemistry The University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Boulevard, Dallas, TX 75235, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: B J
authors.initials: BJ
authors.lastname: Canagarajah
authors.forename: J C
authors.initials: JC
authors.lastname: Boehm
authors.forename: S
authors.initials: S
authors.lastname: Kassisà
authors.forename: M H
authors.initials: MH
authors.lastname: Cobb
authors.forename: P R
authors.initials: PR
authors.lastname: Young
authors.forename: S
authors.initials: S
authors.lastname: Abdel-Meguid
authors.forename: J L
authors.initials: JL
authors.lastname: Adams
authors.forename: E J
authors.initials: EJ
authors.lastname: Goldsmith
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain / Q000187:drug effects; D002454:Cell Differentiation; D002455:Cell Division; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007701:Kinetin; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011687:Purines; D011725:Pyridines; D011743:Pyrimidines; C115502:SB 216995; C115503:SB 218655; C110631:SB 220025; C090046:olomoucine; D000255:Adenosine Triphosphate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D007701:Kinetin