4yv8

From Proteopedia

(Difference between revisions)

Revision as of 08:00, 21 May 2019

Crystal structure of cathepsin K bound to the covalent inhibitor lichostatinal

Structural highlights

4yv8 is a 2 chain structure with sequence from Human and Actinomycete 095-35. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:	, ,
Related:	4yva
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

Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach.

Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts.,Aguda AH, Lavallee V, Cheng P, Bott TM, Meimetis LG, Law S, Nguyen NT, Williams DE, Kaleta J, Villanueva I, Davies J, Andersen RJ, Brayer GD, Bromme D J Nat Prod. 2016 Aug 26;79(8):1962-70. doi: 10.1021/acs.jnatprod.6b00215. Epub, 2016 Aug 6. PMID:27498895^[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
↑ Aguda AH, Lavallee V, Cheng P, Bott TM, Meimetis LG, Law S, Nguyen NT, Williams DE, Kaleta J, Villanueva I, Davies J, Andersen RJ, Brayer GD, Bromme D. Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts. J Nat Prod. 2016 Aug 26;79(8):1962-70. doi: 10.1021/acs.jnatprod.6b00215. Epub, 2016 Aug 6. PMID:27498895 doi:http://dx.doi.org/10.1021/acs.jnatprod.6b00215

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4yv8"

@@ Line 1: / Line 1: @@
 ==Crystal structure of cathepsin K bound to the covalent inhibitor lichostatinal==
-<StructureSection load='4yv8' size='340' side='right' caption='[[4yv8]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='4yv8' size='340' side='right'caption='[[4yv8]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4yv8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Actinomycete_095-35 Actinomycete 095-35]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YV8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YV8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4yv8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Actinomycete_095-35 Actinomycete 095-35]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YV8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YV8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=AG2:AGMATINE'>AG2</scene>, <scene name='pdbligand=RGL:ARGINAL'>RGL</scene>, <scene name='pdbligand=URE:UREA'>URE</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yva|4yva]]</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=4yv8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yv8 OCA], [http://pdbe.org/4yv8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yv8 RCSB], [http://www.ebi.ac.uk/pdbsum/4yv8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yv8 ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 </div>
 <div class="pdbe-citations 4yv8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cathepsin 3D structures|Cathepsin 3D structures]]
 == References ==
 <references/>
@@ Line 29: / Line 33: @@
 [[Category: Actinomycete 095-35]]
 [[Category: Cathepsin K]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Aguda, A H]]
 [[Category: Brayer, G D]]

4yv8

From Proteopedia

Revision as of 08:00, 21 May 2019

Crystal structure of cathepsin K bound to the covalent inhibitor lichostatinal

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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