5j94

Human cathepsin K mutant C25S in complex with the allosteric effector NSC13345

spinqualitylabelsall models 5j94, resolution 2.22Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5j94 is a 1 chain structure. This structure supersedes the now removed PDB entry 4leg. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1XF, SO4 Activity: Cathepsin K, with EC number 3.4.22.38 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum 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 Allosteric modifiers have the potential to fine-tune enzyme activity. Therefore, targeting allosteric sites is gaining increasing recognition as a strategy in drug design. Here we report the use of computational methods for the discovery of the first small-molecule allosteric inhibitor of the collagenolytic cysteine peptidase cathepsin K, a major target for the treatment of osteoporosis. The molecule NSC13345 is identified by high-throughput docking of compound libraries to surface sites on the peptidase that are connected to the active site by an evolutionarily conserved network of residues (protein sector). The crystal structure of the complex shows that NSC13345 binds to a novel allosteric site on cathepsin K. The compound acts as a hyperbolic mixed modifier in the presence of a synthetic substrate, it completely inhibits collagen degradation and has good selectivity for cathepsin K over related enzymes. Altogether, these properties qualify our methodology and NSC13345 as promising candidates for allosteric drug design. A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods.,Novinec M, Korenc M, Caflisch A, Ranganathan R, Lenarcic B, Baici A Nat Commun. 2014 Feb 11;5:3287. doi: 10.1038/ncomms4287. PMID:24518821 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA