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6qbs

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Revision as of 08:24, 3 April 2019

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

Structural highlights

6qbs is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	CTSK, CTSO, CTSO2 (HUMAN)
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.^[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

Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation ( kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K.,Mons E, Jansen IDC, Loboda J, van Doodewaerd BR, Hermans J, Verdoes M, van Boeckel CAA, van Veelen PA, Turk B, Turk D, Ovaa H J Am Chem Soc. 2019 Feb 27;141(8):3507-3514. doi: 10.1021/jacs.8b11027. Epub 2019, Feb 14. PMID:30689386^[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
↑ Mons E, Jansen IDC, Loboda J, van Doodewaerd BR, Hermans J, Verdoes M, van Boeckel CAA, van Veelen PA, Turk B, Turk D, Ovaa H. The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K. J Am Chem Soc. 2019 Feb 27;141(8):3507-3514. doi: 10.1021/jacs.8b11027. Epub 2019, Feb 14. PMID:30689386 doi:http://dx.doi.org/10.1021/jacs.8b11027

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6qbs"

@@ Line 1: / Line 1: @@
 ==The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K==
-<StructureSection load='6qbs' size='340' side='right'  caption='[[6qbs]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
+<StructureSection load='6qbs' size='340' side='right'caption='[[6qbs]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[6qbs]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QBS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QBS FirstGlance]. <br>
@@ Line 28: / Line 28: @@
 [[Category: Cathepsin K]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Boeckel, C A.A van]]
 [[Category: Doodewaerd, B R.van]]

6qbs

From Proteopedia

Revision as of 08:24, 3 April 2019

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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