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PDBsum entry 1s9i

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
1s9i
Jmol
Contents
Protein chain
303 a.a. *
Ligands
ATP ×2
5EA ×2
Metals
_MG ×2
* Residue conservation analysis
PDB id:
1s9i
Name: Transferase
Title: X-ray structure of the human mitogen-activated protein kinase kinase 2 (mek2)in a complex with ligand and mgatp
Structure: Dual specificity mitogen-activated protein kinase kinase 2. Chain: a, b. Synonym: map kinase kinase 2, mapkk 2, erk activator kinase 2, mapk/erk kinase 2, mek2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: map2k2, prkmk2, mek2, mkk2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
3.20Å     R-factor:   0.294     R-free:   0.364
Authors: J.F.Ohren,H.Chen,A.Pavlovsky,C.Whitehead,C.Yan,P.Mcconnell, A.Delaney,D.T.Dudley,J.Sebolt-Leopold,C.A.Hasemann
Key ref:
J.F.Ohren et al. (2004). Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol, 11, 1192-1197. PubMed id: 15543157 DOI: 10.1038/nsmb859
Date:
04-Feb-04     Release date:   23-Nov-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P36507  (MP2K2_HUMAN) -  Dual specificity mitogen-activated protein kinase kinase 2
Seq:
Struc:
400 a.a.
303 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.12.2  - Mitogen-activated protein kinase kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
Bound ligand (Het Group name = ATP)
corresponds exactly
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
DOI no: 10.1038/nsmb859 Nat Struct Mol Biol 11:1192-1197 (2004)
PubMed id: 15543157  
 
 
Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.
J.F.Ohren, H.Chen, A.Pavlovsky, C.Whitehead, E.Zhang, P.Kuffa, C.Yan, P.McConnell, C.Spessard, C.Banotai, W.T.Mueller, A.Delaney, C.Omer, J.Sebolt-Leopold, D.T.Dudley, I.K.Leung, C.Flamme, J.Warmus, M.Kaufman, S.Barrett, H.Tecle, C.A.Hasemann.
 
  ABSTRACT  
 
MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Three-dimensional representations of the ternary complex of MEK1 bound to PD318088 and MgATP. (a) Two views of the MEK1 protein kinase structure with the N-terminal lobe on top, the C-terminal lobe at the bottom and the kinase active site occupied by MgATP and inhibitor located in the hinge region. The -helical regions of the protein are cyan, the -sheet regions are green, the ATP cofactor is pink, the magnesium atom is magenta and PD318088 is gold. The figures are labeled according to standard kinase nomenclature and were produced with Ribbons14, 15, 40. (b) View of the MEK1 active site looking down through the N terminus. The surface is cut away to reveal the inhibitor and ATP-binding pocket and is color-coded by hydrophobicity, with the most hydrophobic regions brown and the least hydrophobic areas green. (c) Detailed view of the interactions involved in orienting the inhibitor and MgATP in the MEK1 structure. The residues located within van der Waals contact are denoted with arcs, whereas hydrogen bonds or electrostatic interactions are denoted by dashed lines.
Figure 3.
Figure 3. Superposition of MEK1 and cAMP-dependent protein kinase (PKA). (a) Two views of MEK1 superimposed on the structure of PKA (PDB entry 1CDK). MEK1 is a ribbon diagram in purple; PKA is a cyan ribbon, and the MEK1 inhibitor and MgATP are not shown for clarity. Left, standard protein kinase view showing that MEK1 and the closed form of PKA align well overall13, 14. Right, the position occupied by helix C in PKA is filled by the MEK activation loop, whereas helix C of MEK1 shifts by 10 toward the N-terminal domain. (b) Close-up view of two different orientations of the MEK1 and PKA overlay. The two views show that the change in the position of helix C in MEK1 is accompanied by the formation of a hydrogen-bonding interaction between the catalytic Glu114 and Ser212. The locations of the comparable side chains are indicated for PKA. In addition, the position occupied by helix C of PKA aligns well with the position of the MEK1 activation loop.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2004, 11, 1192-1197) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21117131 C.Dalvit, and A.Vulpetti (2011).
Fluorine-protein interactions and ¹⁹F NMR isotropic chemical shifts: An empirical correlation with implications for drug design.
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A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.
  Nature, 472, 366-369.
PDB code: 2y4i
21215374 E.C.O'Shaughnessy, S.Palani, J.J.Collins, and C.A.Sarkar (2011).
Tunable signal processing in synthetic MAP kinase cascades.
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21125676 E.Vakiani, and D.B.Solit (2011).
KRAS and BRAF: drug targets and predictive biomarkers.
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21509657 H.Liang, T.Liu, F.Chen, Z.Liu, and S.Liu (2011).
A full-length 3D structure for MAPK/ERK kinase 2 (MEK2).
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21326325 K.W.Lee, A.M.Bode, and Z.Dong (2011).
Molecular targets of phytochemicals for cancer prevention.
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21264348 R.E.Iacob, J.Zhang, N.S.Gray, and J.R.Engen (2011).
Allosteric interactions between the myristate- and ATP-site of the Abl kinase.
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21283106 T.Force, and K.L.Kolaja (2011).
Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes.
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21336309 Y.Kubota, P.O'Grady, H.Saito, and M.Takekawa (2011).
Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation.
  Nat Cell Biol, 13, 282-291.  
20001213 C.A.Lipinski, and J.C.Loftus (2010).
Targeting Pyk2 for therapeutic intervention.
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20472680 C.A.Pratilas, and D.B.Solit (2010).
Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response.
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20632993 C.C.Lee, Y.Jia, N.Li, X.Sun, K.Ng, E.Ambing, M.Y.Gao, S.Hua, C.Chen, S.Kim, P.Y.Michellys, S.A.Lesley, J.L.Harris, and G.Spraggon (2010).
Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain.
  Biochem J, 430, 425-437.
PDB codes: 3l9p 3lcs 3lct
20149254 C.Frémin, and S.Meloche (2010).
From basic research to clinical development of MEK1/2 inhibitors for cancer therapy.
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20070239 D.X.Hou, and T.Kumamoto (2010).
Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling.
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20509038 M.Kudo (2010).
Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice.
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20336692 M.Rabiller, M.Getlik, S.Klüter, A.Richters, S.Tückmantel, J.R.Simard, and D.Rauh (2010).
Proteus in the world of proteins: conformational changes in protein kinases.
  Arch Pharm (Weinheim), 343, 193-206.  
20154661 O.Fedorov, S.Müller, and S.Knapp (2010).
The (un)targeted cancer kinome.
  Nat Chem Biol, 6, 166-169.  
20609406 P.Workman, and I.Collins (2010).
Probing the probes: fitness factors for small molecule tools.
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20621483 R.Wimmer, and M.Baccarini (2010).
Partner exchange: protein-protein interactions in the Raf pathway.
  Trends Biochem Sci, 35, 660-668.  
20199123 S.Ciavarella, A.Milano, F.Dammacco, and F.Silvestris (2010).
Targeted therapies in cancer.
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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
20886116 W.I.Wu, W.C.Voegtli, H.L.Sturgis, F.P.Dizon, G.P.Vigers, and B.J.Brandhuber (2010).
Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition.
  PLoS One, 5, e12913.
PDB code: 3o96
20221486 Z.N.Rezvani, R.J.Mayer, and W.C.Chan (2010).
5-Carboxyfluorescein tagged N-phenylanthranilamide as a tracer reagent for fluorescence polarization: a robust method to screen MAPK pathway allosteric inhibitors.
  Chem Commun (Camb), 46, 2043-2045.  
19404317 A.A.Rambal, Z.L.Panaguiton, L.Kramer, S.Grant, and H.Harada (2009).
MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.
  Leukemia, 23, 1744-1754.  
18936176 A.M.deCathelineau, and G.M.Bokoch (2009).
Inactivation of rho GTPases by statins attenuates anthrax lethal toxin activity.
  Infect Immun, 77, 348-359.  
19788418 A.S.Gillings, K.Balmanno, C.M.Wiggins, M.Johnson, and S.J.Cook (2009).
Apoptosis and autophagy: BIM as a mediator of tumour cell death in response to oncogene-targeted therapeutics.
  FEBS J, 276, 6050-6062.  
19376813 C.Anastasaki, A.L.Estep, R.Marais, K.A.Rauen, and E.E.Patton (2009).
Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.
  Hum Mol Genet, 18, 2543-2554.  
  18523868 C.García-Echeverría (2009).
Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways.
  Purinergic Signal, 5, 117-125.  
19915144 C.M.Emery, K.G.Vijayendran, M.C.Zipser, A.M.Sawyer, L.Niu, J.J.Kim, C.Hatton, R.Chopra, P.A.Oberholzer, M.B.Karpova, L.E.MacConaill, J.Zhang, N.S.Gray, W.R.Sellers, R.Dummer, and L.A.Garraway (2009).
MEK1 mutations confer resistance to MEK and B-RAF inhibition.
  Proc Natl Acad Sci U S A, 106, 20411-20416.  
19282848 D.Dankort, D.P.Curley, R.A.Cartlidge, B.Nelson, A.N.Karnezis, W.E.Damsky, M.J.You, R.A.DePinho, M.McMahon, and M.Bosenberg (2009).
Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.
  Nat Genet, 41, 544-552.  
19153083 D.Meng, M.J.Lynch, E.Huston, M.Beyermann, J.Eichhorst, D.R.Adams, E.Klusmann, M.D.Houslay, and G.S.Baillie (2009).
MEK1 Binds Directly to {beta}Arrestin1, Influencing Both Its Phosphorylation by ERK and the Timing of Its Isoprenaline-stimulated Internalization.
  J Biol Chem, 284, 11425-11435.  
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.  
19644735 H.Low, C.S.Chua, and T.S.Sim (2009).
Regulation of Plasmodium falciparum Pfnek3 relies on phosphorylation at its activation loop and at threonine 82.
  Cell Mol Life Sci, 66, 3081-3090.  
19204698 I.Nobeli, A.D.Favia, and J.M.Thornton (2009).
Protein promiscuity and its implications for biotechnology.
  Nat Biotechnol, 27, 157-167.  
19104514 J.Zhang, P.L.Yang, and N.S.Gray (2009).
Targeting cancer with small molecule kinase inhibitors.
  Nat Rev Cancer, 9, 28-39.  
19876042 L.K.Chico, L.J.Van Eldik, and D.M.Watterson (2009).
Targeting protein kinases in central nervous system disorders.
  Nat Rev Drug Discov, 8, 892-909.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
19638505 L.Xu, Y.Ding, W.J.Catalona, X.J.Yang, W.F.Anderson, B.Jovanovic, K.Wellman, J.Killmer, X.Huang, K.A.Scheidt, R.B.Montgomery, and R.C.Bergan (2009).
MEK4 function, genistein treatment, and invasion of human prostate cancer cells.
  J Natl Cancer Inst, 101, 1141-1155.  
19901082 M.Yamamoto, D.M.Standley, S.Takashima, H.Saiga, M.Okuyama, H.Kayama, E.Kubo, H.Ito, M.Takaura, T.Matsuda, D.Soldati-Favre, and K.Takeda (2009).
A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3.
  J Exp Med, 206, 2747-2760.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
19244237 S.Han, A.Mistry, J.S.Chang, D.Cunningham, M.Griffor, P.C.Bonnette, H.Wang, B.A.Chrunyk, G.E.Aspnes, D.P.Walker, A.D.Brosius, and L.Buckbinder (2009).
Structural Characterization of Proline-rich Tyrosine Kinase 2 (PYK2) Reveals a Unique (DFG-out) Conformation and Enables Inhibitor Design.
  J Biol Chem, 284, 13193-13201.
PDB codes: 3fzo 3fzp 3fzr 3fzs 3fzt
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
19362540 W.M.Old, J.B.Shabb, S.Houel, H.Wang, K.L.Couts, C.Y.Yen, E.S.Litman, C.H.Croy, K.Meyer-Arendt, J.G.Miranda, R.A.Brown, E.S.Witze, R.E.Schweppe, K.A.Resing, and N.G.Ahn (2009).
Functional proteomics identifies targets of phosphorylation by B-Raf signaling in melanoma.
  Mol Cell, 34, 115-131.  
19141286 X.Min, R.Akella, H.He, J.M.Humphreys, S.E.Tsutakawa, S.J.Lee, J.A.Tainer, M.H.Cobb, and E.J.Goldsmith (2009).
The structure of the MAP2K MEK6 reveals an autoinhibitory dimer.
  Structure, 17, 96.
PDB code: 3enm
19651986 Y.D.Shaul, G.Gibor, A.Plotnikov, and R.Seger (2009).
Specific phosphorylation and activation of ERK1c by MEK1b: a unique route in the ERK cascade.
  Genes Dev, 23, 1779-1790.  
19306398 Y.Li, and A.G.Palmer (2009).
Domain swapping in the kinase superfamily: OSR1 joins the mix.
  Protein Sci, 18, 678-681.  
18239682 A.C.Pike, P.Rellos, F.H.Niesen, A.Turnbull, A.W.Oliver, S.A.Parker, B.E.Turk, L.H.Pearl, and S.Knapp (2008).
Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites.
  EMBO J, 27, 704-714.
PDB codes: 2j51 2j7t 2j90 2jfl 2jfm 2uv2
19010912 C.A.Pratilas, A.J.Hanrahan, E.Halilovic, Y.Persaud, J.Soh, D.Chitale, H.Shigematsu, H.Yamamoto, A.Sawai, M.Janakiraman, B.S.Taylor, W.Pao, S.Toyooka, M.Ladanyi, A.Gazdar, N.Rosen, and D.B.Solit (2008).
Genetic predictors of MEK dependence in non-small cell lung cancer.
  Cancer Res, 68, 9375-9383.  
18397888 E.Greggio, I.Zambrano, A.Kaganovich, A.Beilina, J.M.Taymans, V.Daniëls, P.Lewis, S.Jain, J.Ding, A.Syed, K.J.Thomas, V.Baekelandt, and M.R.Cookson (2008).
The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation.
  J Biol Chem, 283, 16906-16914.  
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
18423407 J.A.McCubrey, M.L.Sokolosky, B.D.Lehmann, J.R.Taylor, P.M.Navolanic, W.H.Chappell, S.L.Abrams, K.M.Stadelman, E.W.Wong, N.Misaghian, S.Horn, J.Bäsecke, M.Libra, F.Stivala, G.Ligresti, A.Tafuri, M.Milella, M.Zarzycki, A.Dzugaj, F.Chiarini, C.Evangelisti, A.M.Martelli, D.M.Terrian, R.A.Franklin, and L.S.Steelman (2008).
Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy.
  Adv Enzyme Regul, 48, 113-135.  
18632602 J.L.Marks, Y.Gong, D.Chitale, B.Golas, M.D.McLellan, Y.Kasai, L.Ding, E.R.Mardis, R.K.Wilson, D.Solit, R.Levine, K.Michel, R.K.Thomas, V.W.Rusch, M.Ladanyi, and W.Pao (2008).
Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma.
  Cancer Res, 68, 5524-5528.  
18767048 K.W.Lee, N.J.Kang, E.A.Rogozin, S.M.Oh, Y.S.Heo, A.Pugliese, A.M.Bode, H.J.Lee, and Z.Dong (2008).
The resveratrol analogue 3,5,3',4',5'-pentahydroxy-trans-stilbene inhibits cell transformation via MEK.
  Int J Cancer, 123, 2487-2496.  
18245498 K.W.Lee, N.J.Kang, Y.S.Heo, E.A.Rogozin, A.Pugliese, M.K.Hwang, G.T.Bowden, A.M.Bode, H.J.Lee, and Z.Dong (2008).
Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine.
  Cancer Res, 68, 946-955.  
18361454 M.A.Dolan, M.Keil, and D.S.Baker (2008).
Comparison of composer and ORCHESTRAR.
  Proteins, 72, 1243-1258.  
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
18183025 M.W.Karaman, S.Herrgard, D.K.Treiber, P.Gallant, C.E.Atteridge, B.T.Campbell, K.W.Chan, P.Ciceri, M.I.Davis, P.T.Edeen, R.Faraoni, M.Floyd, J.P.Hunt, D.J.Lockhart, Z.V.Milanov, M.J.Morrison, G.Pallares, H.K.Patel, S.Pritchard, L.M.Wodicka, and P.P.Zarrinkar (2008).
A quantitative analysis of kinase inhibitor selectivity.
  Nat Biotechnol, 26, 127-132.  
19139002 N.J.Kang, K.W.Lee, J.Y.Kwon, M.K.Hwang, E.A.Rogozin, Y.S.Heo, A.M.Bode, H.J.Lee, and Z.Dong (2008).
Delphinidin attenuates neoplastic transformation in JB6 Cl41 mouse epidermal cells by blocking Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling.
  Cancer Prev Res (Phila), 1, 522-531.  
18068683 R.Akella, T.M.Moon, and E.J.Goldsmith (2008).
Unique MAP Kinase binding sites.
  Biochim Biophys Acta, 1784, 48-55.  
18681747 R.J.Orton, O.E.Sturm, A.Gormand, W.Wolch, and D.R.Gilbert (2008).
Computational modelling reveals feedback redundancy within the epidermal growth factor receptor/extracellular-signal regulated kinase signalling pathway.
  IET Syst Biol, 2, 173-183.  
18055465 S.F.Bellon, P.Kaplan-Lefko, Y.Yang, Y.Zhang, J.Moriguchi, K.Rex, C.W.Johnson, P.E.Rose, A.M.Long, A.B.O'Connor, Y.Gu, A.Coxon, T.S.Kim, A.Tasker, T.L.Burgess, and I.Dussault (2008).
c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations.
  J Biol Chem, 283, 2675-2683.
PDB codes: 2rfn 2rfs
18617014 T.Force, and R.Kerkelä (2008).
Cardiotoxicity of the new cancer therapeutics--mechanisms of, and approaches to, the problem.
  Drug Discov Today, 13, 778-784.  
18470943 Y.Aoki, T.Niihori, Y.Narumi, S.Kure, and Y.Matsubara (2008).
The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders.
  Hum Mutat, 29, 992.  
18167536 Y.H.Hao, Y.Wang, D.Burdette, S.Mukherjee, G.Keitany, E.Goldsmith, and K.Orth (2008).
Structural Requirements for Yersinia YopJ Inhibition of MAP Kinase Pathways.
  PLoS ONE, 3, e1375.  
17993409 A.Crespo, and A.Fernández (2007).
Kinase packing defects as drug targets.
  Drug Discov Today, 12, 917-923.  
17496914 A.J.Whitmarsh, and R.J.Davis (2007).
Role of mitogen-activated protein kinase kinase 4 in cancer.
  Oncogene, 26, 3172-3184.  
17728773 A.O.Wilkie (2007).
Cancer drugs to treat birth defects.
  Nat Genet, 39, 1057-1059.  
17314031 E.R.Park, S.T.Eblen, and A.D.Catling (2007).
MEK1 activation by PAK: a novel mechanism.
  Cell Signal, 19, 1488-1496.  
17631144 F.Zhu, T.A.Zykova, B.S.Kang, Z.Wang, M.C.Ebeling, Y.Abe, W.Y.Ma, A.M.Bode, and Z.Dong (2007).
Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells.
  Gastroenterology, 133, 219-231.  
17482503 G.Tortora, R.Bianco, G.Daniele, F.Ciardiello, J.A.McCubrey, M.R.Ricciardi, L.Ciuffreda, F.Cognetti, A.Tafuri, and M.Milella (2007).
Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies.
  Drug Resist Updat, 10, 81.  
17500509 H.Al-Ali, T.J.Ragan, X.Gao, and T.K.Harris (2007).
Reconstitution of modular PDK1 functions on trans-splicing of the regulatory PH and catalytic kinase domains.
  Bioconjug Chem, 18, 1294-1302.  
17881352 J.E.Trosky, Y.Li, S.Mukherjee, G.Keitany, H.Ball, and K.Orth (2007).
VopA inhibits ATP binding by acetylating the catalytic loop of MAPK kinases.
  J Biol Chem, 282, 34299-34305.  
17989929 J.H.Van Drie (2007).
Computer-aided drug design: the next 20 years.
  J Comput Aided Mol Des, 21, 591-601.  
17724030 N.J.Kang, K.W.Lee, E.A.Rogozin, Y.Y.Cho, Y.S.Heo, A.M.Bode, H.J.Lee, and Z.Dong (2007).
Equol, a metabolite of the soybean isoflavone daidzein, inhibits neoplastic cell transformation by targeting the MEK/ERK/p90RSK/activator protein-1 pathway.
  J Biol Chem, 282, 32856-32866.  
18077363 O.Fedorov, B.Marsden, V.Pogacic, P.Rellos, S.Müller, A.N.Bullock, J.Schwaller, M.Sundström, and S.Knapp (2007).
A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
  Proc Natl Acad Sci U S A, 104, 20523-20528.
PDB code: 2j2i
17496923 P.J.Roberts, and C.J.Der (2007).
Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.
  Oncogene, 26, 3291-3310.  
17526574 S.Legewie, B.Schoeberl, N.Blüthgen, and H.Herzel (2007).
Competing docking interactions can bring about bistability in the MAPK cascade.
  Biophys J, 93, 2279-2288.  
17540843 X.Y.Pei, Y.Dai, S.Tenorio, J.Lu, H.Harada, P.Dent, and S.Grant (2007).
MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism.
  Blood, 110, 2092-2101.  
17396111 Y.Huang, N.A.Noble, J.Zhang, C.Xu, and W.A.Border (2007).
Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells.
  Kidney Int, 72, 45-52.  
17366577 Y.Narumi, Y.Aoki, T.Niihori, G.Neri, H.Cavé, A.Verloes, C.Nava, M.I.Kavamura, N.Okamoto, K.Kurosawa, R.C.Hennekam, L.C.Wilson, G.Gillessen-Kaesbach, D.Wieczorek, P.Lapunzina, H.Ohashi, Y.Makita, I.Kondo, S.Tsuchiya, E.Ito, K.Sameshima, K.Kato, S.Kure, and Y.Matsubara (2007).
Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome.
  Am J Med Genet A, 143, 799-807.  
16273091 D.B.Solit, L.A.Garraway, C.A.Pratilas, A.Sawai, G.Getz, A.Basso, Q.Ye, J.M.Lobo, Y.She, I.Osman, T.R.Golub, J.Sebolt-Leopold, W.R.Sellers, and N.Rosen (2006).
BRAF mutation predicts sensitivity to MEK inhibition.
  Nature, 439, 358-362.  
16415863 F.J.Adrián, Q.Ding, T.Sim, A.Velentza, C.Sloan, Y.Liu, G.Zhang, W.Hur, S.Ding, P.Manley, J.Mestan, D.Fabbro, and N.S.Gray (2006).
Allosteric inhibitors of Bcr-abl-dependent cell proliferation.
  Nat Chem Biol, 2, 95.  
17108987 I.Collins, and P.Workman (2006).
New approaches to molecular cancer therapeutics.
  Nat Chem Biol, 2, 689-700.  
15979847 S.Grewal, D.M.Molina, and L.Bardwell (2006).
Mitogen-activated protein kinase (MAPK)-docking sites in MAPK kinases function as tethers that are crucial for MAPK regulation in vivo.
  Cell Signal, 18, 123-134.  
16879720 S.Pelech (2006).
Dimerization in protein kinase signaling.
  J Biol, 5, 12.  
17085044 Z.Shi, K.A.Resing, and N.G.Ahn (2006).
Networks for the allosteric control of protein kinases.
  Curr Opin Struct Biol, 16, 686-692.  
16260599 J.Seyfried, X.Wang, G.Kharebava, and C.Tournier (2005).
A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway.
  Mol Cell Biol, 25, 9820-9828.  
16028302 W.Jahnke, M.J.Blommers, C.Fernández, C.Zwingelstein, and R.Amstutz (2005).
Strategies for the NMR-based identification and optimization of allosteric protein kinase inhibitors.
  Chembiochem, 6, 1607-1610.  
15975507 Z.A.Knight, and K.M.Shokat (2005).
Features of selective kinase inhibitors.
  Chem Biol, 12, 621-637.  
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