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PDBsum entry 1stc
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protein ligands Protein-protein interface(s) links
Complex (transferase/inhibitor) PDB id
1stc

 

 

 

 

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Contents
Protein chains
336 a.a. *
17 a.a. *
Ligands
STU
Waters ×142
* Residue conservation analysis
PDB id:
1stc
Name: Complex (transferase/inhibitor)
Title: Camp-dependent protein kinase, alpha-catalytic subunit in complex with staurosporine
Structure: Camp-dependent protein kinase. Chain: e. Fragment: catalytic subunit. Synonym: capk, protein kinase a, pka c-alpha. Engineered: yes. Protein kinase inhibitor. Chain: i. Fragment: inhibitory domain. Synonym: pki, pki-alpha.
Source: Bos taurus. Cattle. Organism_taxid: 9913. Cell_line: bl21. Organ: heart. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
2.30Å     R-factor:   0.208     R-free:   0.330
Authors: L.Prade,R.A.Engh,A.Girod,V.Kinzel,R.Huber,D.Bossemeyer
Key ref:
L.Prade et al. (1997). Staurosporine-induced conformational changes of cAMP-dependent protein kinase catalytic subunit explain inhibitory potential. Structure, 5, 1627-1637. PubMed id: 9438863
Date:
10-Oct-97     Release date:   25-Feb-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha from Bos taurus
Seq:
Struc: 		351 a.a.
336 a.a.*
Protein chain
Pfam   ArchSchema ?
P61926  (IPKA_RABIT) -  cAMP-dependent protein kinase inhibitor alpha from Oryctolagus cuniculus
Seq:
Struc: 		76 a.a.
17 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain E: E.C.2.7.11.11  - cAMP-dependent protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      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+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
Structure 5:1627-1637 (1997)
PubMed id: 9438863  
 
 
Staurosporine-induced conformational changes of cAMP-dependent protein kinase catalytic subunit explain inhibitory potential.
L.Prade, R.A.Engh, A.Girod, V.Kinzel, R.Huber, D.Bossemeyer.
 
  ABSTRACT  
 
BACKGROUND: Staurosporine inhibits most protein kinases at low nanomolar concentrations. As most tyrosine kinases, along with many serine/threonine kinases, are either proto oncoproteins or are involved in oncogenic signaling, the development of protein kinase inhibitors is a primary goal of cancer research. Staurosporine and many of its derivatives have significant biological effects, and are being tested as anticancer drugs. To understand in atomic detail the mode of inhibition and the parameters of high-affinity binding of staurosporine to protein kinases, the molecule was cocrystallized with the catalytic subunit of cAMP-dependent protein kinase. RESULTS: The crystal structure of the protein kinase catalytic subunit with staurosporine bound to the adenosine pocket shows considerable induced-fit rearrangement of the enzyme and a unique open conformation. The inhibitor mimics several aspects of adenosine binding, including both polar and nonpolar interactions with enzyme residues, and induces conformational changes of neighboring enzyme residues. CONCLUSIONS: The results explain the high inhibitory potency of staurosporine, and also illustrate the flexibility of the protein kinase active site. The structure, therefore, is not only useful for the design of improved anticancer therapeutics and signaling drugs, but also provides a deeper understanding of the conformational flexibility of the protein kinase.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21439031 L.Rosenbaum, G.Hinselmann, A.Jahn, and A.Zell (2011).
Interpreting linear support vector machine models with heat map molecule coloring.
  J Cheminform, 3, 11.  
20848666 M.Sodeoka, and K.Dodo (2010).
Development of selective inhibitors of necrosis.
  Chem Rec, 10, 308-314.  
20336234 O.A.Gani, and R.A.Engh (2010).
Protein kinase inhibition of clinically important staurosporine analogues.
  Nat Prod Rep, 27, 489-498.  
20059362 B.Larson, P.Banks, H.Zegzouti, and S.A.Goueli (2009).
A Simple and robust automated kinase profiling platform using luminescent ADP accumulation technology.
  Assay Drug Dev Technol, 7, 573-584.  
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.  
19523156 D.Mitzner, S.E.Dudek, N.Studtrucker, D.Anhlan, I.Mazur, J.Wissing, L.Jänsch, L.Wixler, K.Bruns, A.Sharma, V.Wray, P.Henklein, S.Ludwig, and U.Schubert (2009).
Phosphorylation of the influenza A virus protein PB1-F2 by PKC is crucial for apoptosis promoting functions in monocytes.
  Cell Microbiol, 11, 1502-1516.  
19290922 R.E.Joseph, and A.H.Andreotti (2009).
Conformational snapshots of Tec kinases during signaling.
  Immunol Rev, 228, 74-92.  
18711718 Z.Huang, and C.F.Wong (2009).
Conformational selection of protein kinase A revealed by flexible-ligand flexible-protein docking.
  J Comput Chem, 30, 631-644.  
17910071 M.D.Jacobs, P.R.Caron, and B.J.Hare (2008).
Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.
  Proteins, 70, 1451-1460.
PDB code: 2pl0
17937911 G.Bunkoczi, E.Salah, P.Filippakopoulos, O.Fedorov, S.Müller, F.Sobott, S.A.Parker, H.Zhang, W.Min, B.E.Turk, and S.Knapp (2007).
Structural and functional characterization of the human protein kinase ASK1.
  Structure, 15, 1215-1226.
PDB code: 2clq
17965187 M.Ikuta, M.Kornienko, N.Byrne, J.C.Reid, S.Mizuarai, H.Kotani, and S.K.Munshi (2007).
Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors.
  Protein Sci, 16, 2626-2635.
PDB codes: 2z7q 2z7r 2z7s
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
17119643 C.Sánchez, C.Méndez, and J.A.Salas (2006).
Indolocarbazole natural products: occurrence, biosynthesis, and biological activity.
  Nat Prod Rep, 23, 1007-1045.  
16531242 H.Yamaguchi, M.Kasa, M.Amano, K.Kaibuchi, and T.Hakoshima (2006).
Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil.
  Structure, 14, 589-600.
PDB code: 2f2u
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.  
16762554 M.Tanaka, S.Sagawa, J.Hoshi, F.Shimoma, K.Yasue, M.Ubukata, T.Ikemoto, Y.Hase, M.Takahashi, T.Sasase, N.Ueda, M.Matsushita, and T.Inaba (2006).
Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCbeta-selective inhibitors.
  Bioorg Med Chem, 14, 5781-5794.  
16917500 R.Jauch, M.K.Cho, S.Jäkel, C.Netter, K.Schreiter, B.Aicher, M.Zweckstetter, H.Jäckle, and M.C.Wahl (2006).
Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment.
  EMBO J, 25, 4020-4032.
PDB codes: 2hw6 2hw7
16699172 S.Bonn, S.Herrero, C.B.Breitenlechner, A.Erlbruch, W.Lehmann, R.A.Engh, M.Gassel, and D.Bossemeyer (2006).
Structural analysis of protein kinase A mutants with Rho-kinase inhibitor specificity.
  J Biol Chem, 281, 24818-24830.
PDB codes: 2gfc 2gnf 2gng 2gnh 2gni 2gnj 2gnl
16761096 T.J.Zhou, L.G.Sun, Y.Gao, and E.J.Goldsmith (2006).
Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine.
  Acta Biochim Biophys Sin (Shanghai), 38, 385-392.
PDB code: 2gcd
16186927 D.Moffat, C.J.Nichols, D.A.Riley, and N.S.Simpkins (2005).
The synthesis of bioactive indolocarbazoles related to K-252a.
  Org Biomol Chem, 3, 2953-2975.  
15657054 M.D.Jacobs, J.Black, O.Futer, L.Swenson, B.Hare, M.Fleming, and K.Saxena (2005).
Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002.
  J Biol Chem, 280, 13728-13734.
PDB codes: 1yhs 1yi3 1yi4
16075446 S.Barrett, S.Bartlett, A.Bolt, A.Ironmonger, C.Joce, A.Nelson, and T.Woodhall (2005).
Configurational stability of bisindolylmaleimide cyclophanes: from conformers to the first configurationally stable, atropisomeric bisindolylmaleimides.
  Chemistry, 11, 6277-6285.  
14962382 D.Komander, G.S.Kular, A.W.Schüttelkopf, M.Deak, K.R.Prakash, J.Bain, M.Elliott, M.Garrido-Franco, A.P.Kozikowski, D.R.Alessi, and D.M.van Aalten (2004).
Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1.
  Structure, 12, 215-226.
PDB codes: 1uu3 1uu7 1uu8 1uu9 1uvr
14766749 K.Brown, J.M.Long, S.C.Vial, N.Dedi, N.J.Dunster, S.B.Renwick, A.J.Tanner, J.D.Frantz, M.A.Fleming, and G.M.Cheetham (2004).
Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors.
  J Biol Chem, 279, 18727-18732.
PDB codes: 1sm2 1snu 1snx
15292186 L.Jin, S.Pluskey, E.C.Petrella, S.M.Cantin, J.C.Gorga, M.J.Rynkiewicz, P.Pandey, J.E.Strickler, R.E.Babine, D.T.Weaver, and K.J.Seidl (2004).
The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors.
  J Biol Chem, 279, 42818-42825.
PDB code: 1u59
14996846 M.Gassel, C.B.Breitenlechner, N.König, R.Huber, R.A.Engh, and D.Bossemeyer (2004).
The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A.
  J Biol Chem, 279, 23679-23690.
PDB code: 1szm
15364937 Z.B.Xu, D.Chaudhary, S.Olland, S.Wolfrom, R.Czerwinski, K.Malakian, L.Lin, M.L.Stahl, D.Joseph-McCarthy, C.Benander, L.Fitz, R.Greco, W.S.Somers, and L.Mosyak (2004).
Catalytic domain crystal structure of protein kinase C-theta (PKCtheta).
  J Biol Chem, 279, 50401-50409.
PDB code: 1xjd
14656443 C.Breitenlechner, M.Gassel, H.Hidaka, V.Kinzel, R.Huber, R.A.Engh, and D.Bossemeyer (2003).
Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity.
  Structure, 11, 1595-1607.
PDB codes: 1q8t 1q8u 1q8w
12869192 E.De Moliner, N.R.Brown, and L.N.Johnson (2003).
Alternative binding modes of an inhibitor to two different kinases.
  Eur J Biochem, 270, 3174-3181.
PDB code: 1p5e
12191603 R.A.Engh, and D.Bossemeyer (2002).
Structural aspects of protein kinase control-role of conformational flexibility.
  Pharmacol Ther, 93, 99.  
12169624 R.M.Biondi, D.Komander, C.C.Thomas, J.M.Lizcano, M.Deak, D.R.Alessi, and D.M.van Aalten (2002).
High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site.
  EMBO J, 21, 4219-4228.
PDB code: 1h1w
11306297 A.C.Bishop, O.Buzko, and K.M.Shokat (2001).
Magic bullets for protein kinases.
  Trends Cell Biol, 11, 167-172.  
11090628 E.H.Walker, M.E.Pacold, O.Perisic, L.Stephens, P.T.Hawkins, M.P.Wymann, and R.L.Williams (2000).
Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.
  Mol Cell, 6, 909-919.
PDB codes: 1e7u 1e7v 1e8w 1e8x 1e8y 1e8z 1e90
10820007 M.Batkin, I.Schvartz, and S.Shaltiel (2000).
Snapping of the carboxyl terminal tail of the catalytic subunit of PKA onto its core: characterization of the sites by mutagenesis.
  Biochemistry, 39, 5366-5373.  
10454194 J.M.Sowadski, L.F.Epstein, L.Lankiewicz, and R.Karlsson (1999).
Conformational diversity of catalytic cores of protein kinases.
  Pharmacol Ther, 82, 157-164.  
10454204 M.E.Noble, and J.A.Endicott (1999).
Chemical inhibitors of cyclin-dependent kinases: insights into design from X-ray crystallographic studies.
  Pharmacol Ther, 82, 269-278.  
10454192 S.S.Taylor, E.Radzio-Andzelm, Madhusudan, X.Cheng, L.Ten Eyck, and N.Narayana (1999).
Catalytic subunit of cyclic AMP-dependent protein kinase: structure and dynamics of the active site cleft.
  Pharmacol Ther, 82, 133-141.  
10404594 X.Zhu, J.L.Kim, J.R.Newcomb, P.E.Rose, D.R.Stover, L.M.Toledo, H.Zhao, and K.A.Morgenstern (1999).
Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors.
  Structure, 7, 651-661.
PDB codes: 1qpc 1qpd 1qpe 1qpj
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 code is shown on the right.

 

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