PDBsum entry 1yi3

Transferase

PDB id: 1yi3

Contents

Protein chain

269 a.a. *

Ligands

LY2

Waters ×134

* Residue conservation analysis

PDB id:

1yi3

Name:

Transferase

Title:

Crystal structure of pim-1 bound to ly294002

Structure:

Proto-oncogene serine/threonine-protein kinase pim-1. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pim1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.50Å R-factor: 0.208 R-free: 0.259

Authors:

M.D.Jacobs,J.Black,O.Futer,L.Swenson,B.Hare,M.Fleming,K.Saxena

Key ref:

M.D.Jacobs et al. (2005). Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002. J Biol Chem, 280, 13728-13734. PubMed id: 15657054 DOI: 10.1074/jbc.M413155200

Date:

11-Jan-05 Release date: 25-Jan-05

Protein chain

P11309  (PIM1_HUMAN) -  Serine/threonine-protein kinase pim-1 from Homo sapiens

Seq: 313 a.a.

Struc: 269 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.M413155200

J Biol Chem 280:13728-13734 (2005)

PubMed id: 15657054

Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002.

M.D.Jacobs, J.Black, O.Futer, L.Swenson, B.Hare, M.Fleming, K.Saxena.

ABSTRACT

Pim-1 is an oncogene-encoded serine/threonine kinase primarily expressed in hematopoietic and germ cell lines. Pim-1 kinase was originally identified in Maloney murine leukemia virus-induced T-cell lymphomas and is associated with multiple cellular functions such as proliferation, survival, differentiation, apoptosis, and tumorigenesis (Wang, Z., Bhattacharya, N., Weaver, M., Petersen, K., Meyer, M., Gapter, L., and Magnuson, N. S. (2001) J. Vet. Sci. 2, 167-179). The crystal structures of Pim-1 complexed with staurosporine and adenosine were determined. Although a typical two-domain serine/threonine protein kinase fold is observed, the inter-domain hinge region is unusual in both sequence and conformation; a two-residue insertion causes the hinge to bulge away from the ATP-binding pocket, and a proline residue in the hinge removes a conserved main chain hydrogen bond donor. Without this hydrogen bond, van der Waals interactions with the hinge serve to position the ligand. The hinge region of Pim-1 resembles that of phosphatidylinositol 3-kinase more closely than it does other protein kinases. Although the phosphatidylinositol 3-kinase inhibitor LY294002 also inhibits Pim-1, the structure of the LY294002.Pim-1 complex reveals a new binding mode that may be general for Ser/Thr kinases.

Selected figure(s)

Figure 2.
FIG. 2. Overall structure of the Pim-1·staurosporine complex. The structure is shown with -sheets as arrows and the -helices as cylinders. The N-terminal domain (dark blue) is shown with the glycine-rich loop drawn in green. The hinge connecting the two domains is colored orange. The C-terminal domain is shown in light blue with the activation loop shown in yellow. Staurosporine (red) is shown in the active site, bound between the Phe^49 side chain (colored gray in the glycine-rich loop) and the hinge region. The salt bridge stabilizing the conformation of the activation loop is formed by residues Asp200 and Arg166 side chains, drawn with gray carbon atoms. The site of phosphorylation, Ser261, is shown. All of the structural figures were prepared with Pymol (54).

Figure 3.
FIG. 3. Ligand interactions with the hinge region: comparison with PKA. Structures of Pim-1 and PKA bound to staurosporine and adenosine were aligned to optimize the superposition of residues adjacent to the hinge regions. The Pim-1 structure is colored by atom type and labeled in black, and PKA is drawn and labeled in pink. Hydrogen bonds are depicted as green dotted lines. The view is rotated 90° from Fig. 2. In this orientation, the glycine-rich loop lies above and in the plane of the page. A, the structures of the PKA·staurosporine (Protein Data Bank code 1STC [PDB] ) and Pim-1·staurosporine complexes. B, Pim-1·adenosine and PKA complexes (Protein Data Bank code 1FMO [PDB] ). C, sequence alignments of hinge regions. Residues that accept and donate hydrogen bonds to the adenine ring of ATP are highlighted in red and blue, respectively.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 13728-13734) copyright 2005.

Figures were selected by an automated process.