4n79

Structure of Cathepsin K-dermatan sulfate complex

spinqualitylabelsall models 4n79, resolution 2.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4n79 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.62Å Ligands: ASG, IDR 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 Cathepsin K is the major collagenolytic protease in bone that facilitates physiological as well as pathological bone degradation. Despite its key role in bone remodeling and for being a highly sought-after drug target for the treatment of osteoporosis, the mechanism of collagen fiber degradation by cathepsin K remained elusive. Here, we report the structure of a collagenolytically active cathepsin K protein dimer. Cathepsin K is organized into elongated C-shaped protease dimers that reveal a putative collagen-binding interface aided by glycosaminoglycans. Molecular modeling of collagen binding to the dimer indicates the participation of nonactive site amino acid residues, Q21 and Q92, in collagen unfolding. Mutations at these sites as well as perturbation of the dimer protein-protein interface completely inhibit cathepsin-K-mediated fiber degradation without affecting the hydrolysis of gelatin or synthetic peptide. Using scanning electron microscopy, we demonstrate the specific binding of cathepsin K at the edge of the fibrillar gap region of collagen fibers, which suggest initial cleavage events at the N- and C-terminal ends of tropocollagen molecules. Edman degradation analysis of collagen fiber degradation products revealed those initial cleavage sites. We propose that one cathepsin K molecule binds to collagen-bound glycosaminoglycans at the gap region and recruits a second protease molecule that provides an unfolding and cleavage mechanism for triple helical collagen. Removal of collagen-associated glycosaminoglycans prevents cathepsin K binding and subsequently fiber hydrolysis. Cathepsin K dimer and glycosaminoglycan binding sites represent novel targeting sites for the development of nonactive site-directed second-generation inhibitors of this important drug target. Structural basis of collagen fiber degradation by cathepsin K.,Aguda AH, Panwar P, Du X, Nguyen NT, Brayer GD, Bromme D Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17474-9. doi:, 10.1073/pnas.1414126111. Epub 2014 Nov 24. PMID:25422423 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cathepsin 3D structures

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