› 4an3

X-ray diffraction
2.1Å resolution

Crystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.

Released:
DOI: 10.2210/pdb4an3/pdb
PDB entry 4an3 coloured by chain, front view.
PDB entry 4an3 coloured by chain, side view.
PDB entry 4an3 coloured by chain, top view.
Source organism: Homo sapiens
Primary publication:
Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973).
Rice KD, Aay N, Anand NK, Blazey CM, Bowles OJ, Bussenius J, Costanzo S, Curtis JK, Defina SC, Dubenko L, Engst S, Joshi AA, Kennedy AR, Kim AI, Koltun ES, Lougheed JC, Manalo JC, Martini JF, Nuss JM, Peto CJ, Tsang TH, Yu P, Johnston S
ACS Med Chem Lett 3 416-21 (2012)
PMID: 24900486

Function and Biology Details

Reaction catalysed: 
ATP + L-seryl/L-threonyl/L-tyrosyl-[protein] = ADP + O-phospho-L-seryl/O-phospho-L-threonyl/O-phospho-L-tyrosyl-[protein]
Biochemical function:
Biological process:
Cellular component:
  • not assigned
Sequence domains:

Structure analysis Details

Assembly composition:
monomeric (preferred)
Assembly name:
PDBe Complex ID:
PDB-CPX-169744 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
Dual specificity mitogen-activated protein kinase kinase 1 Chain: A
Molecule details ›
Chain: A
Length: 301 amino acids
Theoretical weight: 33.61 KDa
Source organism: Homo sapiens
Expression system: Spodoptera frugiperda
UniProt:
  • Canonical: Q02750 (Residues: 61-392; Coverage: 74%)
Gene names: MAP2K1, MEK1, PRKMK1
Sequence domains: Protein kinase domain
Structure domains:

Ligands and Environments

3 bound ligands:
Ligand MG 1 x MG
Ligand ATP 1 x ATP
Ligand 5Y0 1 x 5Y0
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: SSRL BEAMLINE BL11-1
Spacegroup: P61
Unit cell:
a: 108.659Å b: 108.659Å c: 50.113Å
α: 90° β: 90° γ: 120°
R-values:
R R work R free
0.229 0.226 0.283
Expression system: Spodoptera frugiperda

Quick links

Citations

18 review citations

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Enzymes.
Alexander et al. (2019)
17 more

5 mentions without citation

Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome.
Zhao et al. (2017)
4 more