PDBsum entry 5fnu

Transcription

PDB id: 5fnu

Contents

Protein chain

288 a.a.

Ligands

L6I

Metals

_CL

Waters ×363

PDB id:

5fnu

Name:

Transcription

Title:

Structure of the keap1 kelch domain in complex with a small molecule inhibitor.

Structure:

Kelch-like ech-associated protein 1. Chain: a. Fragment: kelch domain, unp residues 322-624. Synonym: cytosolic inhibitor of nrf2, inrf2, keap1. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.78Å R-factor: 0.168 R-free: 0.205

Authors:

T.G.Davies,W.E.Wixted,J.E.Coyle,C.Griffiths-Jones,K.Hearn, R.Mcmenamin,D.Norton,S.J.Rich,C.Richardson,G.Saxty,H.M.G.Willems, A.J.Woolford,J.E.Cottom,J.Kou,J.G.Yonchuk,H.G.Feldser,Y.Sanchez, J.P.Foley,B.J.Bolognese,G.Logan,P.L.Podolin,H.Yan,J.F.Callahan, T.D.Heightman,J.K.Kerns

Key ref:

T.G.Davies et al. (2016). Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery. J Med Chem, 59, 3991-4006. PubMed id: 27031670 DOI: 10.1021/acs.jmedchem.6b00228

Date:

16-Nov-15 Release date: 13-Apr-16

Protein chain

Q9Z2X8  (KEAP1_MOUSE) -  Kelch-like ECH-associated protein 1 from Mus musculus

Seq: 624 a.a.

Struc: 288 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.6b00228

J Med Chem 59:3991-4006 (2016)

PubMed id: 27031670

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.

T.G.Davies, W.E.Wixted, J.E.Coyle, C.Griffiths-Jones, K.Hearn, R.McMenamin, D.Norton, S.J.Rich, C.Richardson, G.Saxty, H.M.Willems, A.J.Woolford, J.E.Cottom, J.P.Kou, J.G.Yonchuk, H.G.Feldser, Y.Sanchez, J.P.Foley, B.J.Bolognese, G.Logan, P.L.Podolin, H.Yan, J.F.Callahan, T.D.Heightman, J.K.Kerns.

ABSTRACT

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.