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PDBsum entry 2uv2
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protein ligands links
Transferase PDB id
2uv2

 

 

 

 

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Contents
Protein chain
287 a.a. *
Ligands
EDO ×5
SCN ×2
GVD
Waters ×148
* Residue conservation analysis
PDB id:
2uv2
Name: Transferase
Title: Crystal structure of human ste20-like kinase bound to 4-(4-(5- cyclopropyl-1h-pyrazol-3-ylamino)-quinazolin-2-ylamino)-phenyl)- acetonitrile
Structure: Ste20-like serine-threonine kinase. Chain: a. Fragment: kinase domain, residues 19-320. Synonym: ste20-like kinase, ste20-related serine/threonine-protein kinase, ste20-related kinase, hslk, serine/threonine-protein kinase 2, ctcl tumor antigen se20-9. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.30Å     R-factor:   0.199     R-free:   0.234
Authors: A.C.W.Pike,P.Rellos,O.Fedorov,T.Keates,E.Salah,P.Savitsky, E.Papagrigoriou,G.Bunkoczi,J.E.Debreczeni,F.Von Delft, C.H.Arrowsmith,A.Edwards,J.Weigelt,M.Sundstrom,S.Knapp
Key ref: A.C.Pike et al. (2008). Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites. Embo J, 27, 704-714. PubMed id: 18239682
Date:
08-Mar-07     Release date:   20-Mar-07    
Supersedes: 2ja0
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9H2G2  (SLK_HUMAN) -  STE20-like serine/threonine-protein kinase from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1235 a.a.
287 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - non-specific serine/threonine 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    
 
 
Embo J 27:704-714 (2008)
PubMed id: 18239682  
 
 
Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites.
A.C.Pike, P.Rellos, F.H.Niesen, A.Turnbull, A.W.Oliver, S.A.Parker, B.E.Turk, L.H.Pearl, S.Knapp.
 
  ABSTRACT  
 
Protein kinase autophosphorylation of activation segment residues is a common regulatory mechanism in phosphorylation-dependent signalling cascades. However, the molecular mechanisms that guarantee specific and efficient phosphorylation of these sites have not been elucidated. Here, we report on three novel and diverse protein kinase structures that reveal an exchanged activation segment conformation. This dimeric arrangement results in an active kinase conformation in trans, with activation segment phosphorylation sites in close proximity to the active site of the interacting protomer. Analytical ultracentrifugation and chemical cross-linking confirmed the presence of dimers in solution. Consensus substrate sequences for each kinase showed that the identified activation segment autophosphorylation sites are non-consensus substrate sites. Based on the presented structural and functional data, a model for specific activation segment phosphorylation at non-consensus substrate sites is proposed that is likely to be common to other kinases from diverse subfamilies.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21390216 E.Sala, L.Guasch, J.Iwaszkiewicz, M.Mulero, M.J.Salvadó, M.Pinent, V.Zoete, A.Grosdidier, S.Garcia-Vallvé, O.Michielin, and G.Pujadas (2011).
Identification of human IKK-2 inhibitors of natural origin (part I): modeling of the IKK-2 kinase domain, virtual screening and activity assays.
  PLoS One, 6, e16903.  
21417343 E.Salah, E.Ugochukwu, A.J.Barr, F.von Delft, S.Knapp, and J.M.Elkins (2011).
Crystal structures of ABL-related gene (ABL2) in complex with imatinib, tozasertib (VX-680), and a type I inhibitor of the triazole carbothioamide class.
  J Med Chem, 54, 2359-2367.
PDB code: 2xyn
21317875 M.M.Ali, T.Bagratuni, E.L.Davenport, P.R.Nowak, M.C.Silva-Santisteban, A.Hardcastle, C.McAndrews, M.G.Rowlands, G.J.Morgan, W.Aherne, I.Collins, F.E.Davies, and L.H.Pearl (2011).
Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response.
  EMBO J, 30, 894-905.
PDB code: 3p23
21497122 T.H.Lee, C.H.Chen, F.Suizu, P.Huang, C.Schiene-Fischer, S.Daum, Y.J.Zhang, A.Goate, R.H.Chen, X.Z.Zhou, and K.P.Lu (2011).
Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function.
  Mol Cell, 42, 147-159.  
  20889563 A.V.Cybulsky, T.Takano, J.Papillon, J.Guillemette, A.M.Herzenberg, and C.R.Kennedy (2010).
Podocyte injury and albuminuria in mice with podocyte-specific overexpression of the Ste20-like kinase, SLK.
  Am J Pathol, 177, 2290-2299.  
20730082 C.J.Record, A.Chaikuad, P.Rellos, S.Das, A.C.Pike, O.Fedorov, B.D.Marsden, S.Knapp, and W.H.Lee (2010).
Structural comparison of human mammalian ste20-like kinases.
  PLoS One, 5, e11905.
PDB code: 3ggf
19854302 J.Eswaran, and S.Knapp (2010).
Insights into protein kinase regulation and inhibition by large scale structural comparison.
  Biochim Biophys Acta, 1804, 429-432.  
19965870 J.M.Steichen, G.H.Iyer, S.Li, S.A.Saldanha, M.S.Deal, V.L.Woods, and S.S.Taylor (2010).
Global consequences of activation loop phosphorylation on protein kinase A.
  J Biol Chem, 285, 3825-3832.  
20453092 L.Nováková, S.Bezousková, P.Pompach, P.Spidlová, L.Sasková, J.Weiser, and P.Branny (2010).
Identification of multiple substrates of the StkP Ser/Thr protein kinase in Streptococcus pneumoniae.
  J Bacteriol, 192, 3629-3638.  
20466062 M.Vedadi, C.H.Arrowsmith, A.Allali-Hassani, G.Senisterra, and G.A.Wasney (2010).
Biophysical characterization of recombinant proteins: a key to higher structural genomics success.
  J Struct Biol, 172, 107-119.  
20124694 T.P.Ko, W.Y.Jeng, C.I.Liu, M.D.Lai, C.L.Wu, W.J.Chang, H.L.Shr, T.J.Lu, and A.H.Wang (2010).
Structures of human MST3 kinase in complex with adenine, ADP and Mn2+.
  Acta Crystallogr D Biol Crystallogr, 66, 145-154.
PDB codes: 3a7f 3a7g 3a7h 3a7i 3a7j
19864428 T.Sunami, N.Byrne, R.E.Diehl, K.Funabashi, D.L.Hall, M.Ikuta, S.B.Patel, J.M.Shipman, R.F.Smith, I.Takahashi, J.Zugay-Murphy, Y.Iwasawa, K.J.Lumb, S.K.Munshi, and S.Sharma (2010).
Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation.
  J Biol Chem, 285, 4587-4594.
PDB codes: 3a60 3a61 3a62
20579309 X.Wu, J.Wang, J.K.Na, Q.Yu, R.C.Moore, F.Zee, S.C.Huber, and R.Ming (2010).
The origin of the non-recombining region of sex chromosomes in Carica and Vasconcellea.
  Plant J, 63, 801-810.  
19489729 A.Edwards (2009).
Large-scale structural biology of the human proteome.
  Annu Rev Biochem, 78, 541-568.  
19079236 A.V.Korennykh, P.F.Egea, A.A.Korostelev, J.Finer-Moore, C.Zhang, K.M.Shokat, R.M.Stroud, and P.Walter (2009).
The unfolded protein response signals through high-order assembly of Ire1.
  Nature, 457, 687-693.
PDB code: 3fbv
19675209 C.J.Storbeck, S.Wagner, P.O'Reilly, M.McKay, R.J.Parks, H.Westphal, and L.A.Sabourin (2009).
The Ldb1 and Ldb2 transcriptional cofactors interact with the Ste20-like kinase SLK and regulate cell migration.
  Mol Biol Cell, 20, 4174-4182.  
19582900 D.Demidov, S.Hesse, A.Tewes, T.Rutten, J.Fuchs, R.K.Ashtiyani, S.Lein, A.Fischer, G.Reuter, and A.Houben (2009).
Aurora1 phosphorylation activity on histone H3 and its cross-talk with other post-translational histone modifications in Arabidopsis.
  Plant J, 59, 221-230.  
19399514 E.Delpire (2009).
The mammalian family of sterile 20p-like protein kinases.
  Pflugers Arch, 458, 953-967.  
19219045 F.Catalanotti, G.Reyes, V.Jesenberger, G.Galabova-Kovacs, R.de Matos Simoes, O.Carugo, and M.Baccarini (2009).
A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal.
  Nat Struct Mol Biol, 16, 294-303.  
19651772 R.Scholz, M.Suter, T.Weimann, C.Polge, P.V.Konarev, R.F.Thali, R.D.Tuerk, B.Viollet, T.Wallimann, U.Schlattner, and D.Neumann (2009).
Homo-oligomerization and activation of AMP-activated protein kinase are mediated by the kinase domain alphaG-helix.
  J Biol Chem, 284, 27425-27437.  
19177573 S.J.Lee, M.H.Cobb, and E.J.Goldsmith (2009).
Crystal structure of domain-swapped STE20 OSR1 kinase domain.
  Protein Sci, 18, 304-313.
PDB code: 3dak
19306398 Y.Li, and A.G.Palmer (2009).
Domain swapping in the kinase superfamily: OSR1 joins the mix.
  Protein Sci, 18, 678-681.  
18787129 A.P.Kornev, S.S.Taylor, and L.F.Ten Eyck (2008).
A helix scaffold for the assembly of active protein kinases.
  Proc Natl Acad Sci U S A, 105, 14377-14382.  
19053485 A.V.Statsuk, D.J.Maly, M.A.Seeliger, M.A.Fabian, W.H.Biggs, D.J.Lockhart, P.P.Zarrinkar, J.Kuriyan, and K.M.Shokat (2008).
Tuning a three-component reaction for trapping kinase substrate complexes.
  J Am Chem Soc, 130, 17568-17574.
PDB code: 3f6x
19008858 C.Mieczkowski, A.T.Iavarone, and T.Alber (2008).
Auto-activation mechanism of the Mycobacterium tuberculosis PknB receptor Ser/Thr kinase.
  EMBO J, 27, 3186-3197.
PDB codes: 3f61 3f69
18715118 E.Mazanka, J.Alexander, B.J.Yeh, P.Charoenpong, D.M.Lowery, M.Yaffe, and E.L.Weiss (2008).
The NDR/LATS family kinase Cbk1 directly controls transcriptional asymmetry.
  PLoS Biol, 6, e203.  
18831043 F.Villa, M.Deak, D.R.Alessi, and D.M.van Aalten (2008).
Structure of the OSR1 kinase, a hypertension drug target.
  Proteins, 73, 1082-1087.
PDB code: 2vwi
18639460 J.Eswaran, M.Soundararajan, R.Kumar, and S.Knapp (2008).
UnPAKing the class differences among p21-activated kinases.
  Trends Biochem Sci, 33, 394-403.  
18818768 J.L.Dermody, J.M.Dreyfuss, J.Villén, B.Ogundipe, S.P.Gygi, P.J.Park, A.S.Ponticelli, C.L.Moore, S.Buratowski, and M.E.Bucheli (2008).
Unphosphorylated SR-like protein Npl3 stimulates RNA polymerase II elongation.
  PLoS ONE, 3, e3273.  
18566589 J.Wu, W.Li, B.P.Craddock, K.W.Foreman, M.J.Mulvihill, Q.S.Ji, W.T.Miller, and S.R.Hubbard (2008).
Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor.
  EMBO J, 27, 1985-1994.
PDB code: 3d94
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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