1yt7: Difference between revisions

Revision as of 08:52, 20 January 2021

Cathepsin K complexed with a constrained ketoamide inhibitor

Structural highlights

1yt7 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	3FC, SO4
Related:	1tu6
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.

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

An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.

P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K.,Barrett DG, Boncek VM, Catalano JG, Deaton DN, Hassell AM, Jurgensen CH, Long ST, McFadyen RB, Miller AB, Miller LR, Payne JA, Ray JA, Samano V, Shewchuk LM, Tavares FX, Wells-Knecht KJ, Willard DH Jr, Wright LL, Zhou HQ Bioorg Med Chem Lett. 2005 Aug 1;15(15):3540-6. PMID:15982880^[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
↑ Barrett DG, Boncek VM, Catalano JG, Deaton DN, Hassell AM, Jurgensen CH, Long ST, McFadyen RB, Miller AB, Miller LR, Payne JA, Ray JA, Samano V, Shewchuk LM, Tavares FX, Wells-Knecht KJ, Willard DH Jr, Wright LL, Zhou HQ. P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K. Bioorg Med Chem Lett. 2005 Aug 1;15(15):3540-6. PMID:15982880 doi:10.1016/j.bmcl.2005.05.062

Proteopedia Page Contributors and Editors (what is this?)

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] Barrett DG, Boncek VM, Catalano JG, Deaton DN, Hassell AM, Jurgensen CH, Long ST, McFadyen RB, Miller AB, Miller LR, Payne JA, Ray JA, Samano V, Shewchuk LM, Tavares FX, Wells-Knecht KJ, Willard DH Jr, Wright LL, Zhou HQ. P2-P3 conformationally constrained ketoamide-based inhibitors of cathepsin K. Bioorg Med Chem Lett. 2005 Aug 1;15(15):3540-6. PMID:15982880 doi:10.1016/j.bmcl.2005.05.062

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[2]

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[5]

@@ Line 1: / Line 1: @@
 ==Cathepsin K complexed with a constrained ketoamide inhibitor==
-<StructureSection load='1yt7' size='340' side='right' caption='[[1yt7]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='1yt7' size='340' side='right'caption='[[1yt7]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1yt7]] is a 1 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=1YT7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1YT7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1yt7]] is a 1 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=1YT7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1YT7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3FC:(1R)-2,2-DIMETHYL-1-({5-[4-(TRIFLUOROMETHYL)PHENYL]-1,3,4-OXADIAZOL-2-YL}METHYL)PROPYL+(1S)-1-{OXO[(2-OXO-1,3-OXAZOLIDIN-3-YL)AMINO]ACETYL}PENTYLCARBAMATE'>3FC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3FC:(1R)-2,2-DIMETHYL-1-({5-[4-(TRIFLUOROMETHYL)PHENYL]-1,3,4-OXADIAZOL-2-YL}METHYL)PROPYL+(1S)-1-{OXO[(2-OXO-1,3-OXAZOLIDIN-3-YL)AMINO]ACETYL}PENTYLCARBAMATE'>3FC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tu6|1tu6]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1tu6|1tu6]]</div></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSK, CTSO, CTSO2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_K Cathepsin K], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.38 3.4.22.38] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1yt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1yt7 OCA], [http://pdbe.org/1yt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1yt7 RCSB], [http://www.ebi.ac.uk/pdbsum/1yt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1yt7 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1yt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1yt7 OCA], [http://pdbe.org/1yt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1yt7 RCSB], [http://www.ebi.ac.uk/pdbsum/1yt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1yt7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 35: / Line 35: @@
 ==See Also==
-*[[Cathepsin|Cathepsin]]
+*[[Cathepsin 3D structures|Cathepsin 3D structures]]
 == References ==
 <references/>
@@ Line 42: / Line 42: @@
 [[Category: Cathepsin K]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Barrett, D G]]
 [[Category: Boncek, V M]]

1yt7: Difference between revisions

Revision as of 08:52, 20 January 2021

Cathepsin K complexed with a constrained ketoamide inhibitor

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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