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PDBsum entry 3e8n
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protein ligands metals links
Transferase PDB id
3e8n

 

 

 

 

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Contents
Protein chain
291 a.a. *
Ligands
ATP
VRA
Metals
_MG
Waters ×65
* Residue conservation analysis
PDB id:
3e8n
Name: Transferase
Title: X-ray structure of the human mitogen-activated protein kinase kinase 1 (mek1) complexed with a potent inhibitor rdea119 and mgatp
Structure: Dual specificity mitogen-activated protein kinase kinase 1. Chain: a. Synonym: map kinase kinase 1, mapkk 1, erk activator kinase 1, mapk/erk kinase 1, mek1. Engineered: yes
Source: Homo sapiens. Organism_taxid: 9606. Gene: mek1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.50Å     R-factor:   0.219     R-free:   0.252
Authors: S.Yan,Z.M.Wang
Key ref: C.Iverson et al. (2009). RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res, 69, 6839-6847. PubMed id: 19706763 DOI: 10.1158/0008-5472.CAN-09-0679
Date:
20-Aug-08     Release date:   01-Sep-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q02750  (MP2K1_HUMAN) -  Dual specificity mitogen-activated protein kinase kinase 1 from Homo sapiens
Seq:
Struc: 		393 a.a.
291 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.2.7.12.2  - mitogen-activated protein kinase 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+
3. L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-seryl-[protein]
Bound ligand (Het Group name = ATP)
corresponds exactly 		+ ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
Bound ligand (Het Group name = ATP)
corresponds exactly 		+ ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
L-tyrosyl-[protein]
Bound ligand (Het Group name = ATP)
corresponds exactly 		+ ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1158/0008-5472.CAN-09-0679 Cancer Res 69:6839-6847 (2009)
PubMed id: 19706763  
 
 
RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.
C.Iverson, G.Larson, C.Lai, L.T.Yeh, C.Dadson, P.Weingarten, T.Appleby, T.Vo, A.Maderna, J.M.Vernier, R.Hamatake, J.N.Miner, B.Quart.
 
  ABSTRACT  
 
The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system-related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21441910 D.F.Brennan, A.C.Dar, N.T.Hertz, W.C.Chao, A.L.Burlingame, K.M.Shokat, and D.Barford (2011).
A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.
  Nature, 472, 366-369.
PDB code: 2y4i
21110380 J.L.Yap, S.Worlikar, A.D.Mackerell, P.Shapiro, and S.Fletcher (2011).
Small-Molecule Inhibitors of the ERK Signaling Pathway: Towards Novel Anticancer Therapeutics.
  ChemMedChem, 6, 38-48.  
21493862 T.M.Holm, J.P.Habashi, J.J.Doyle, D.Bedja, Y.Chen, C.van Erp, M.E.Lindsay, D.Kim, F.Schoenhoff, R.D.Cohn, B.L.Loeys, C.J.Thomas, S.Patnaik, J.J.Marugan, D.P.Judge, and H.C.Dietz (2011).
Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice.
  Science, 332, 358-361.  
20149254 C.Frémin, and S.Meloche (2010).
From basic research to clinical development of MEK1/2 inhibitors for cancer therapy.
  J Hematol Oncol, 3, 8.  
20920162 Q.Chang, M.S.Chapman, J.N.Miner, and D.W.Hedley (2010).
Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts.
  BMC Cancer, 10, 515.  
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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