5MKR

HSP72-NBD bound to compound TCI 8 - Tyr15 in up-conformation

Summary for 5MKR

• Entry DOI: 10.2210/pdb5mkr/pdb
• Descriptor: Heat shock 70 kDa protein 1A, 3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-azanyl-8-[(4-chlorophenyl)methylamino]purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]propyl prop-2-enoate, CITRATE ANION, ... (4 entities in total)
• Functional Keywords: irreversible inhibitor, chaperone, lysine modification
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P0DMV8
• Total number of polymer chains: 1
• Total formula weight: 43873.93

Authors

Pettinger, J.,Westwood, I.M.,Cronin, N.,Le Bihan, Y.-V.,Van Montfort, R.L.M. (deposition date: 2016-12-05, release date: 2017-03-01, Last modification date: 2024-05-01)

Primary citation

Pettinger, J.,Le Bihan, Y.V.,Widya, M.,van Montfort, R.L.,Jones, K.,Cheeseman, M.D.
An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.
Angew. Chem. Int. Ed. Engl., 56:3536-3540, 2017

PubMed Abstract: The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine-56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs.

PubMed: 28225177
DOI: 10.1002/anie.201611907

Experimental method

X-RAY DIFFRACTION (1.87 Å)