5MKR

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

5MKR の概要

• エントリーDOI: 10.2210/pdb5mkr/pdb
• 分子名称: 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)
• 機能のキーワード: irreversible inhibitor, chaperone, lysine modification
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : P0DMV8
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43873.93

構造登録者

Pettinger, J.,Westwood, I.M.,Cronin, N.,Le Bihan, Y.-V.,Van Montfort, R.L.M. (登録日: 2016-12-05, 公開日: 2017-03-01, 最終更新日: 2024-05-01)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.87 Å)