title: Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase.
abstract: Pim-1 kinase is a member of a distinct class of serine/threonine kinases consisting of Pim-1, Pim-2, and Pim-3. Pim kinases are highly homologous to one another and share a unique consensus hinge region sequence, ER-PXPX, with its two proline residues separated by a non-conserved residue, but they (Pim kinases) have <30% sequence identity with other kinases. Pim-1 has been implicated in both cytokine-induced signal transduction and the development of lymphoid malignancies. We have determined the crystal structures of apo Pim-1 kinase and its AMP-PNP (5'-adenylyl-beta,gamma-imidodiphosphate) complex to 2.1-angstroms resolutions. The structures reveal the following. 1) The kinase adopts a constitutively active conformation, and extensive hydrophobic and hydrogen bond interactions between the activation loop and the catalytic loop might be the structural basis for maintaining such a conformation. 2) The hinge region has a novel architecture and hydrogen-bonding pattern, which not only expand the ATP pocket but also serve to establish unambiguously the alignment of the Pim-1 hinge region with that of other kinases. 3) The binding mode of AMP-PNP to Pim-1 kinase is unique and does not involve a critical hinge region hydrogen bond interaction. Analysis of the reported Pim-1 kinase-domain structures leads to a hypothesis as to how Pim kinase activity might be regulated in vivo.
authors.affiliation: Departments of Medicinal Chemistry and Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Research and Development, 175 Briar Ridge Rd., Ridgefield, CT 06877, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Qian
authors.forename: Lian
authors.initials: L
authors.lastname: Wang
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Hickey
authors.forename: Joey
authors.initials: J
authors.lastname: Studts
authors.forename: Kevin
authors.initials: K
authors.lastname: Barringer
authors.forename: Charline
authors.initials: C
authors.lastname: Peng
authors.forename: Anthony
authors.initials: A
authors.lastname: Kronkaitis
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Andre
authors.initials: A
authors.lastname: White
authors.forename: Sheenah
authors.initials: S
authors.lastname: Mische
authors.forename: Bennett
authors.initials: B
authors.lastname: Farmer
mesh_terms: D000266:Adenylyl Imidodiphosphate / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1; D013329:Structure-Activity Relationship
chemical_list: D001059:Apoproteins; D011518:Proto-Oncogene Proteins; D000266:Adenylyl Imidodiphosphate; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1