7QBM

Structure of the activation intermediate of cathepsin K in complex with the 3-cyano-3-aza-beta-amino acid inhibitor Gu2602

7QBM の概要

• エントリーDOI: 10.2210/pdb7qbm/pdb
• 分子名称: Cathepsin K, ~{tert}-butyl ~{N}-[iminomethyl-[2-[methyl-(phenylmethyl)amino]-2-oxidanylidene-ethyl]amino]carbamate, ACETATE ION, ... (6 entities in total)
• 機能のキーワード: cathepsin k, protease inhibitor, cyanohydrazide warhead, azadipeptide nitrile, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 33063.61

構造登録者

Benysek, J.,Busa, M.,Mares, M. (登録日: 2021-11-19, 公開日: 2022-01-26, 最終更新日: 2024-11-13)

主引用文献

Benysek, J.,Busa, M.,Rubesova, P.,Fanfrlik, J.,Lepsik, M.,Brynda, J.,Matouskova, Z.,Bartz, U.,Horn, M.,Gutschow, M.,Mares, M.
Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes.
J Enzyme Inhib Med Chem, 37:515-526, 2022

PubMed Abstract: Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile and a 3-cyano-3-aza-β-amino acid . Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.

PubMed: 35144520
DOI: 10.1080/14756366.2021.2024527

実験手法

X-RAY DIFFRACTION (1.88 Å)