3E8N

X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) complexed with a potent inhibitor RDEA119 and MgATP

PDB DOI: https://doi.org/10.2210/pdb3E8N/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2008-08-20 Released: 2009-09-01
Deposition Author(s): Yan, S., Wang, Z.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free: 0.252
R-Value Work: 0.219

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.

Iverson, C., Larson, G., Lai, C., Yeh, L.T., Dadson, C., Weingarten, P., Appleby, T., Vo, T., Maderna, A., Vernier, J.M., Hamatake, R., Miner, J.N., Quart, B.

(2009) Cancer Res 69: 6839-6847

PubMed: 19706763 Search on PubMed
DOI: https://doi.org/10.1158/0008-5472.CAN-09-0679
Primary Citation of Related Structures:
3E8N

PubMed 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.

Organizational Affiliation

Research and Development, Ardea Biosciences, Inc., San Diego, California 92121, USA.

Macromolecule Content

Total Structure Weight: 39.03 kDa
Atom Count: 2,403
Modelled Residue Count: 291
Deposited Residue Count: 341
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dual specificity mitogen-activated protein kinase kinase 1	A	341	Homo sapiens	Mutation(s): 0 Gene Names: MEK1 EC: 2.7.12.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02750 (Homo sapiens) Explore Q02750 Go to UniProtKB: Q02750
PHAROS: Q02750 GTEx: ENSG00000169032
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q02750
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
VRA Query on VRA Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A]	D [auth A]	N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[(2S)-2,3-dihydroxypropyl]cyclopropanesulfonamide C₁₉ H₂₀ F₃ I N₂ O₅ S RDSACQWTXKSHJT-NSHDSACASA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
ATP Query on ATP Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	ADENOSINE-5'-TRIPHOSPHATE C₁₀ H₁₆ N₅ O₁₃ P₃ ZKHQWZAMYRWXGA-KQYNXXCUSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
VRA	Binding MOAD: 3E8N	IC50: 19 (nM) from 1 assay(s)
VRA	PDBBind: 3E8N	IC50: 19 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.50 Å
R-Value Free: 0.252
R-Value Work: 0.219
Space Group: P 6₂

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 82.261	α = 90
b = 82.261	β = 90
c = 129.778	γ = 120

Software Package:

Software Name	Purpose
CrystalClear	data collection
CNS	refinement
DENZO	data reduction
SCALEPACK	data scaling
CNS	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2009-09-01

Deposition Author(s):

Yan, S.

Wang, Z.M.

Revision History (Full details and data files)

Version 1.0: 2009-09-01
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2023-08-30
Changes: Data collection, Database references, Derived calculations, Refinement description