7nxm
From Proteopedia
Structure of human cathepsin K in complex with the selective activity-based probe Gu3416
Structural highlights
Disease[CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.[1] [2] [3] [4] Function[CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Publication Abstract from PubMedThe cysteine protease cathepsin K is a target for the treatment of diseases associated with high bone turnover. Cathepsin K is mainly expressed in osteoclasts and responsible for the destruction of the proteinaceous components of the bone matrix. We designed various fluorescent activity-based probes (ABPs) and their precursors that bind to and inactivate cathepsin K. ABP 25 exhibited extraordinary potency (kinac/Ki = 35,300 M(-1)s(-1)) and selectivity for human cathepsin K. Crystal structures of cathepsin K in complex with ABP 25 and its nonfluorescent precursor 21 were determined to characterize the binding mode of this new type of acrylamide-based Michael acceptor with the particular orientation of the dibenzylamine moiety to the primed subsite region. The cyanine-5 containing probe 25 allowed for sensitive detection of cathepsin K, selective visualization in complex proteomes, and live cell imaging of a human osteosarcoma cell line, underlining its applicability in a pathophysiological environment. An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity.,Lemke C, Benysek J, Brajtenbach D, Breuer C, Jilkova A, Horn M, Busa M, Ulrychova L, Illies A, Kubatzky KF, Bartz U, Mares M, Gutschow M J Med Chem. 2021 Sep 23;64(18):13793-13806. doi: 10.1021/acs.jmedchem.1c01178., Epub 2021 Sep 2. PMID:34473502[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Cathepsin K | Human | Large Structures | Benysek, J | Busa, M | Gutschow, M | Lemke, C | Mares, M | Acrylamide inhibitor | Activity-based probe | Complex | Hydrolase | Inhibitor
