› 4an9

X-ray diffraction
2.8Å resolution

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

Released:
DOI: 10.2210/pdb4an9/pdb
PDB entry 4an9 coloured by chain, front view.
PDB entry 4an9 coloured by chain, side view.
PDB entry 4an9 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 ACP 1 x ACP
Ligand MG 1 x MG
Ligand 2P7 1 x 2P7
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: SSRL BEAMLINE BL9-1
Spacegroup: P61
Unit cell:
a: 108.653Å b: 108.653Å c: 49.394Å
α: 90° β: 90° γ: 120°
R-values:
R R work R free
0.205 0.2 0.313
Expression system: Spodoptera frugiperda

Quick links

Citations

17 review citations

The clinical development of MEK inhibitors.
Zhao et al. (2014)
16 more

3 mentions without citation

EMBER-Embedding Multiple Molecular Fingerprints for Virtual Screening.
Mendolia et al. (2022)
2 more