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PDBsum entry 1yi3

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Transferase PDB id
1yi3
Jmol PyMol
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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P11309  (PIM1_HUMAN) -  Serine/threonine-protein kinase pim-1
Seq:
Struc:
404 a.a.
269 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* 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.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     negative regulation of apoptotic process   2 terms 
  Biochemical function     protein kinase activity     3 terms  

 

 
    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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21233853 D.Finlay, and D.A.Cantrell (2011).
Metabolism, migration and memory in cytotoxic T cells.
  Nat Rev Immunol, 11, 109-117.  
21150935 M.C.Nawijn, A.Alendar, and A.Berns (2011).
For better or for worse: the role of Pim oncogenes in tumorigenesis.
  Nat Rev Cancer, 11, 23-34.  
21276940 O.Fedorov, K.Huber, A.Eisenreich, P.Filippakopoulos, O.King, A.N.Bullock, D.Szklarczyk, L.J.Jensen, D.Fabbro, J.Trappe, U.Rauch, F.Bracher, and S.Knapp (2011).
Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing.
  Chem Biol, 18, 67-76.
PDB codes: 2vag 2wu6 2wu7
20203306 G.A.Borillo, M.Mason, P.Quijada, M.Völkers, C.Cottage, M.McGregor, S.Din, K.Fischer, N.Gude, D.Avitabile, S.Barlow, R.Alvarez, S.Truffa, R.Whittaker, M.S.Glassy, A.B.Gustafsson, S.Miyamoto, C.C.Glembotski, R.A.Gottlieb, J.H.Brown, and M.A.Sussman (2010).
Pim-1 kinase protects mitochondrial integrity in cardiomyocytes.
  Circ Res, 106, 1265-1274.  
  20145274 L.Brault, C.Gasser, F.Bracher, K.Huber, S.Knapp, and J.Schwaller (2010).
PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers.
  Haematologica, 95, 1004-1015.  
20919829 N.S.Magnuson, Z.Wang, G.Ding, and R.Reeves (2010).
Why target PIM1 for cancer diagnosis and treatment?
  Future Oncol, 6, 1461-1478.  
19841674 A.N.Bullock, S.Russo, A.Amos, N.Pagano, H.Bregman, J.E.Debreczeni, W.H.Lee, F.von Delft, E.Meggers, and S.Knapp (2009).
Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor.
  PLoS One, 4, e7112.
PDB code: 2iwi
19674907 C.D.Shomin, S.C.Meyer, and I.Ghosh (2009).
Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA): optimization and selectivity profiling.
  Bioorg Med Chem, 17, 6196-6202.  
19458359 J.Tamburini, A.S.Green, V.Bardet, N.Chapuis, S.Park, L.Willems, M.Uzunov, N.Ifrah, F.Dreyfus, C.Lacombe, P.Mayeux, and D.Bouscary (2009).
Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia.
  Blood, 114, 1618-1627.  
19673671 M.A.Sussman (2009).
Mitochondrial integrity: preservation through Akt/Pim-1 kinase signaling in the cardiomyocyte.
  Expert Rev Cardiovasc Ther, 7, 929-938.  
19209957 M.E.Feldman, B.Apsel, A.Uotila, R.Loewith, Z.A.Knight, D.Ruggero, and K.M.Shokat (2009).
Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
  PLoS Biol, 7, e38.  
19279164 S.Miyamoto, M.Rubio, and M.A.Sussman (2009).
Nuclear and mitochondrial signalling Akts in cardiomyocytes.
  Cardiovasc Res, 82, 272-285.  
18768389 S.A.Didichenko, N.Spiegl, T.Brunner, and C.A.Dahinden (2008).
IL-3 induces a Pim1-dependent antiapoptotic pathway in primary human basophils.
  Blood, 112, 3949-3958.  
17983802 H.Katoh, H.Ojima, A.Kokubu, S.Saito, T.Kondo, T.Kosuge, F.Hosoda, I.Imoto, J.Inazawa, S.Hirohashi, and T.Shibata (2007).
Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets.
  Gastroenterology, 133, 1475-1486.  
18037896 J.A.Muraski, M.Rota, Y.Misao, J.Fransioli, C.Cottage, N.Gude, G.Esposito, F.Delucchi, M.Arcarese, R.Alvarez, S.Siddiqi, G.N.Emmanuel, W.Wu, K.Fischer, J.J.Martindale, C.C.Glembotski, A.Leri, J.Kajstura, N.Magnuson, A.Berns, R.M.Beretta, S.R.Houser, E.M.Schaefer, P.Anversa, and M.A.Sussman (2007).
Pim-1 regulates cardiomyocyte survival downstream of Akt.
  Nat Med, 13, 1467-1475.  
17406720 N.Pagano, J.Maksimoska, H.Bregman, D.S.Williams, R.D.Webster, F.Xue, and E.Meggers (2007).
Ruthenium half-sandwich complexes as protein kinase inhibitors: derivatization of the pyridocarbazole pharmacophore ligand.
  Org Biomol Chem, 5, 1218-1227.
PDB code: 2oi4
17920279 T.Crabbe, M.J.Welham, and S.G.Ward (2007).
The PI3K inhibitor arsenal: choose your weapon!
  Trends Biochem Sci, 32, 450-456.  
17119643 C.Sánchez, C.Méndez, and J.A.Salas (2006).
Indolocarbazole natural products: occurrence, biosynthesis, and biological activity.
  Nat Prod Rep, 23, 1007-1045.  
16381041 J.E.Debreczeni, A.N.Bullock, G.E.Atilla, D.S.Williams, H.Bregman, S.Knapp, and E.Meggers (2006).
Ruthenium half-sandwich complexes bound to protein kinase Pim-1.
  Angew Chem Int Ed Engl, 45, 1580-1585.  
16453361 U.Schatzschneider, and N.Metzler-Nolte (2006).
New principles in medicinal organometallic chemistry.
  Angew Chem Int Ed Engl, 45, 1504-1507.  
16239903 C.J.Fox, P.S.Hammerman, and C.B.Thompson (2005).
Fuel feeds function: energy metabolism and the T-cell response.
  Nat Rev Immunol, 5, 844-852.  
16200194 R.Amaravadi, and C.B.Thompson (2005).
The survival kinases Akt and Pim as potential pharmacological targets.
  J Clin Invest, 115, 2618-2624.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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