7nxm

Structure of human cathepsin K in complex with the selective activity-based probe Gu3416Structure of human cathepsin K in complex with the selective activity-based probe Gu3416

Structural highlights

7nxm 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 1.72Å
Ligands:	,
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.^[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 PubMed

The 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

↑ Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996 Aug 30;273(5279):1236-8. PMID:8703060
↑ Gelb BD, Willner JP, Dunn TM, Kardon NB, Verloes A, Poncin J, Desnick RJ. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Am J Hum Genet. 1998 Apr;62(4):848-54. PMID:9529353 doi:S0002-9297(07)60977-X
↑ Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C. Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res. 1999 Oct;14(10):1649-53. PMID:10491211
↑ Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA. Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet. 2000 Jun;8(6):431-6. PMID:10878663 doi:10.1038/sj.ejhg.5200481
↑ 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. An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity. J Med Chem. 2021 Sep 23;64(18):13793-13806. doi: 10.1021/acs.jmedchem.1c01178., Epub 2021 Sep 2. PMID:34473502 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01178

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OCA

[1] Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996 Aug 30;273(5279):1236-8. PMID:8703060

[2] Gelb BD, Willner JP, Dunn TM, Kardon NB, Verloes A, Poncin J, Desnick RJ. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Am J Hum Genet. 1998 Apr;62(4):848-54. PMID:9529353 doi:S0002-9297(07)60977-X

[3] Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C. Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res. 1999 Oct;14(10):1649-53. PMID:10491211

[4] Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA. Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet. 2000 Jun;8(6):431-6. PMID:10878663 doi:10.1038/sj.ejhg.5200481

[5] 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. An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity. J Med Chem. 2021 Sep 23;64(18):13793-13806. doi: 10.1021/acs.jmedchem.1c01178., Epub 2021 Sep 2. PMID:34473502 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01178

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7nxm

Structure of human cathepsin K in complex with the selective activity-based probe Gu3416Structure of human cathepsin K in complex with the selective activity-based probe Gu3416

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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7nxm

Structure of human cathepsin K in complex with the selective activity-based probe Gu3416Structure of human cathepsin K in complex with the selective activity-based probe Gu3416

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

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