PDBsum entry 2wtk

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protein ligands Protein-protein interface(s) links
Transferase/metal-binding protein PDB id
Protein chains
321 a.a. *
311 a.a. *
285 a.a. *
268 a.a. *
ANP ×4
Waters ×102
* Residue conservation analysis
PDB id:
Name: Transferase/metal-binding protein
Title: Structure of the heterotrimeric lkb1-stradalpha-mo25alpha complex
Structure: Calcium-binding protein 39. Chain: a, d. Synonym: mo25alpha, protein mo25. Engineered: yes. Ste20-related kinase adapter protein alpha. Chain: b, e. Fragment: pseudokinase domain, residues 59-431. Synonym: stradalpha, strad alpha, ste20-related adapter pro serologically defined breast cancer antigen ny-br-96.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
2.65Å     R-factor:   0.240     R-free:   0.291
Authors: E.Zeqiraj,D.M.F.Van Aalten
Key ref:
E.Zeqiraj et al. (2009). Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science, 326, 1707-1711. PubMed id: 19892943 DOI: 10.1126/science.1178377
16-Sep-09     Release date:   15-Dec-09    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q9Y376  (CAB39_HUMAN) -  Calcium-binding protein 39
341 a.a.
321 a.a.
Protein chains
Pfam   ArchSchema ?
Q7RTN6  (STRAA_HUMAN) -  STE20-related kinase adapter protein alpha
431 a.a.
311 a.a.
Protein chain
Pfam   ArchSchema ?
Q15831  (STK11_HUMAN) -  Serine/threonine-protein kinase STK11
433 a.a.
285 a.a.*
Protein chain
Pfam   ArchSchema ?
Q15831  (STK11_HUMAN) -  Serine/threonine-protein kinase STK11
433 a.a.
268 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 7 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains C, F: E.C.  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
Bound ligand (Het Group name = ANP)
matches with 81.25% similarity
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     protein complex   5 terms 
  Biological process     signal transduction by phosphorylation   15 terms 
  Biochemical function     protein binding     8 terms  


DOI no: 10.1126/science.1178377 Science 326:1707-1711 (2009)
PubMed id: 19892943  
Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation.
E.Zeqiraj, B.M.Filippi, M.Deak, D.R.Alessi, D.M.van Aalten.
The LKB1 tumor suppressor is a protein kinase that controls the activity of adenosine monophosphate-activated protein kinase (AMPK). LKB1 activity is regulated by the pseudokinase STRADalpha and the scaffolding protein MO25alpha through an unknown, phosphorylation-independent, mechanism. We describe the structure of the core heterotrimeric LKB1-STRADalpha-MO25alpha complex, revealing an unusual allosteric mechanism of LKB1 activation. STRADalpha adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRADalpha and MO25alpha promote the active conformation of LKB1, which is stabilized by MO25alpha interacting with the LKB1 activation loop. This previously undescribed mechanism of kinase activation may be relevant to understanding the evolution of other pseudokinases. The structure also reveals how mutations found in Peutz-Jeghers syndrome and in various sporadic cancers impair LKB1 function.
  Selected figure(s)  
Figure 1.
View larger version (69K): [in this window] [in a new window] Fig. 1. Overall structure and LKB1-STRAD -MO25 complex interactions. (A) Cartoon representation of the heterotrimeric complex and two bound AMP-PNP molecules are shown in stick representations (LKB1, yellow carbons; STRAD , magenta carbons). The -P for AMP-PNP bound to LKB1 was not visible because of disorder. The WEF motif at the C terminus of STRAD , for which connectivity could not be unambiguously identified because of disorder of the linkers, is shown in cyan. (B) Detailed view of LKB1-STRAD interaction. STRAD p+1 and EF- F loops are colored green and orange, respectively. (C) Interaction of the LKB1 CFT[L] with STRAD and LKB1 N and C lobes. The proline-rich CFT[L] is colored red. (D) Detailed view of LKB1-MO25 interaction. The LKB1 activation loop is colored magenta. (E) Detailed view of LKB1 A-loop interactions. Backbone interactions are shown as dashed lines. Residues Asp^208, Thr^230, and Ser^232 mutated in PJS are labeled and their side chains displayed. A salt bridge between Glu^199 and Lys^175 (dashed line) represents the interaction of the LKB1 activation segment with its catalytic loop (C-loop). The corresponding interaction found in PKA (PDB ID 1ATP [PDB] ) between the phosphorylated Thr^197 (pThr) and Arg^165 is also shown, with PKA residues represented as transparent sticks (carbon atoms colored cyan). The typical "activatory" threonine (Thr^202) present in the LKB1 A-loop is labeled. Secondary structure elements are labeled according to the structure of PKA (15).
Figure 3.
View larger version (97K): [in this window] [in a new window] Fig. 3. Map of oncogenic mutations on the LKB1 kinase domain and the CFT[L]. (A) Location of LKB1 residues that are mutated in PJS and other types of cancer. The CFT[L] region is colored red. Dashed lines represent areas that were not well defined by electron density. (B) Surface-exposed residues that are mutated in PJS and other types of cancer.
  The above figures are reprinted by permission from the AAAs: Science (2009, 326, 1707-1711) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22801495 D.P.Denning, V.Hatch, and H.R.Horvitz (2012).
Programmed elimination of cells by caspase-independent cell extrusion in C. elegans.
  Nature, 488, 226-230.  
22797597 M.Gloerich, J.P.Ten Klooster, M.J.Vliem, T.Koorman, F.J.Zwartkruis, H.Clevers, and J.L.Bos (2012).
Rap2A links intestinal cell polarity to brush border formation.
  Nat Cell Biol, 14, 793-801.  
20974850 A.Morén, E.Raja, C.H.Heldin, and A.Moustakas (2011).
Negative regulation of TGFβ signaling by the kinase LKB1 and the scaffolding protein LIP1.
  J Biol Chem, 286, 341-353.  
21423148 B.M.Filippi, Los Heros, Y.Mehellou, I.Navratilova, R.Gourlay, M.Deak, L.Plater, R.Toth, E.Zeqiraj, and D.R.Alessi (2011).
MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases.
  EMBO J, 30, 1730-1741.  
21241696 B.Y.Shorning, and A.R.Clarke (2011).
LKB1 loss of function studied in vivo.
  FEBS Lett, 585, 958-966.  
21841788 D.Ungureanu, J.Wu, T.Pekkala, Y.Niranjan, C.Young, O.N.Jensen, C.F.Xu, T.A.Neubert, R.C.Skoda, S.R.Hubbard, and O.Silvennoinen (2011).
The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling.
  Nat Struct Mol Biol, 18, 971-976.  
21192934 K.Vaahtomeri, and T.P.Mäkelä (2011).
Molecular mechanisms of tumor suppression by LKB1.
  FEBS Lett, 585, 944-951.  
  21557502 R.Insolera, S.Chen, and S.H.Shi (2011).
Par proteins and neuronal polarity.
  Dev Neurobiol, 71, 483-494.  
20971646 S.S.Taylor, and A.P.Kornev (2011).
Protein kinases: evolution of dynamic regulatory proteins.
  Trends Biochem Sci, 36, 65-77.  
20133840 B.G.Hale, P.S.Kerry, D.Jackson, B.L.Precious, A.Gray, M.J.Killip, R.E.Randall, and R.J.Russell (2010).
Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein.
  Proc Natl Acad Sci U S A, 107, 1954-1959.
PDB code: 3l4q
21074407 E.Zeqiraj, and D.M.van Aalten (2010).
Pseudokinases-remnants of evolution or key allosteric regulators?
  Curr Opin Struct Biol, 20, 772-781.  
20424326 K.A.Orlova, W.E.Parker, G.G.Heuer, V.Tsai, J.Yoon, M.Baybis, R.S.Fenning, K.Strauss, and P.B.Crino (2010).
STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.
  J Clin Invest, 120, 1591-1602.  
20925120 K.E.Marshall, A.J.Tomasini, K.Makky, S.N Kumar, and A.N.Mayer (2010).
Dynamic Lkb1-TORC1 signaling as a possible mechanism for regulating the endoderm-intestine transition.
  Dev Dyn, 239, 3000-3012.  
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.