title: Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase.
abstract: The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated in normal cells, whereas deregulated c-Kit kinase activity is implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have an autoinhibitory function; however the precise mechanism by which c-Kit is maintained in an autoinhibited state is not known. We report the 1.9-A resolution crystal structure of native c-Kit kinase in an autoinhibited conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the activated structure. A 1.6-A crystal structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in an autoinhibited state. Together, these results provide a structural basis for understanding c-Kit kinase autoinhibition and will facilitate the structure-guided design of specific inhibitors that target the activated and autoinhibited conformations of c-Kit kinase.
authors.affiliation: Syrrx, Inc., San Diego, California, 92121, USA. clifford.mol@syrrx.com
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Mol
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Schneider
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Skene
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Kraus
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Scheibe
authors.forename: Gyorgy P
authors.initials: GP
authors.lastname: Snell
authors.forename: Hua
authors.initials: H
authors.lastname: Zou
authors.forename: Bi-Ching
authors.initials: BC
authors.lastname: Sang
authors.forename: Keith P
authors.initials: KP
authors.lastname: Wilson
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000737:chemistry; D001549:Benzamides; D020134:Catalytic Domain; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010879:Piperazines / Q000494:pharmacology*; D011487:Protein Conformation; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; D001224:Aspartic Acid; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases