5z5o

Structure of Pycnonodysostosis disease related I249T mutant of human cathepsin K

spinqualitylabelsall models 5z5o, resolution 1.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5z5o is a 2 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 1.92Å Ligands: CL, EDO, GOL, MPD, NA, PEG, SEB, SO4 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 Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of collagenolytic activity of CTSK leading to an autosomal recessive bone disorder called pycnodysostosis. Though a number of pycnodysostotic missense mutations have been reported, underlying mechanism of the disease is not clear. In this study we investigated in vitro six recombinant pycnodysostosis related mutants of human CTSK (G79E, I249T, G243E, G303E, G319C and Q187P). While all the mutants, like wild-type, show similar high level of expression in E. coli, four of them (G79E, G303E, G319C and Q187P) are inactive, unstable and spontaneously degrade during purification process. In contrast, proteolytic/collagenolytic activity, zymogen activation kinetics and stability of G243E and I249T mutants are nominally affected. Crystal structure of I249T at 1.92A resolution shows that the mutation in R-domain causes conformational changes of a surface loop in L-domain though the catalytic cleft remains unaltered. Molecular simulation, normal mode analysis and Fluorescence life time measurement eliminated the possibility that the change in L-domain surface loop orientation is a crystallization artefact. CD-based thermal melting profile indicates that stability of I249T is significantly higher than wild-type. Our studies first time reports that pycnodysostosis are not always correlated with either a complete loss of proteolytic activity or at least collagenolytic activity due to mutation of CTSK gene. The first crystal structure of a pycnodysostotic mutant (I249T) provides critical information that may pave new avenues towards understanding the disease at molecular level. This article is protected by copyright. All rights reserved. Not all pycnodysostosis-related mutants of human cathepsin K are inactive: Crystal structure and biochemical studies of an active mutant I249T.,Roy S, Das Chakraborty S, Biswas S FEBS J. 2018 Sep 10. doi: 10.1111/febs.14655. PMID:30199612 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cathepsin 3D structures

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