2r6n

Crystal structure of a pyrrolopyrimidine inhibitor in complex with human Cathepsin KCrystal structure of a pyrrolopyrimidine inhibitor in complex with human Cathepsin K

Structural highlights

2r6n 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 1.95Å
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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.

Novel scaffold for cathepsin K inhibitors.,Teno N, Miyake T, Ehara T, Irie O, Sakaki J, Ohmori O, Gunji H, Matsuura N, Masuya K, Hitomi Y, Nonomura K, Horiuchi M, Gohda K, Iwasaki A, Umemura I, Tada S, Kometani M, Iwasaki G, Cowan-Jacob SW, Missbach M, Lattmann R, Betschart C Bioorg Med Chem Lett. 2007 Nov 15;17(22):6096-100. Epub 2007 Sep 15. PMID:17911019^[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
↑ Teno N, Miyake T, Ehara T, Irie O, Sakaki J, Ohmori O, Gunji H, Matsuura N, Masuya K, Hitomi Y, Nonomura K, Horiuchi M, Gohda K, Iwasaki A, Umemura I, Tada S, Kometani M, Iwasaki G, Cowan-Jacob SW, Missbach M, Lattmann R, Betschart C. Novel scaffold for cathepsin K inhibitors. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6096-100. Epub 2007 Sep 15. PMID:17911019 doi:10.1016/j.bmcl.2007.09.047

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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] Teno N, Miyake T, Ehara T, Irie O, Sakaki J, Ohmori O, Gunji H, Matsuura N, Masuya K, Hitomi Y, Nonomura K, Horiuchi M, Gohda K, Iwasaki A, Umemura I, Tada S, Kometani M, Iwasaki G, Cowan-Jacob SW, Missbach M, Lattmann R, Betschart C. Novel scaffold for cathepsin K inhibitors. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6096-100. Epub 2007 Sep 15. PMID:17911019 doi:10.1016/j.bmcl.2007.09.047

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