4yv8

Crystal structure of cathepsin K bound to the covalent inhibitor lichostatinal

spinqualitylabelsall models 4yv8, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4yv8 is a 2 chain structure with sequence from [1] and Actinomycete 095-35. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: SO4 NonStd Res: AG2, RGL, URE Related: 4yva Activity: Cathepsin K, with EC number 3.4.22.38 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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 PubMed Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach. Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts.,Aguda AH, Lavallee V, Cheng P, Bott TM, Meimetis LG, Law S, Nguyen NT, Williams DE, Kaleta J, Villanueva I, Davies J, Andersen RJ, Brayer GD, Bromme D J Nat Prod. 2016 Aug 26;79(8):1962-70. doi: 10.1021/acs.jnatprod.6b00215. Epub, 2016 Aug 6. PMID:27498895 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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