3kjf: Difference between revisions
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==Caspase 3 Bound to a covalent inhibitor== | |||
<StructureSection load='3kjf' size='340' side='right'caption='[[3kjf]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3kjf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KJF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KJF FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B92:(3S)-3-({[(5S,10AS)-2-{(2S)-4-CARBOXY-2-[(PHENYLACETYL)AMINO]BUTYL}-1,3-DIOXO-2,3,5,7,8,9,10,10A-OCTAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]CINNOLIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC+ACID'>B92</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3kjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kjf OCA], [https://pdbe.org/3kjf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kjf RCSB], [https://www.ebi.ac.uk/pdbsum/3kjf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kjf ProSAT]</span></td></tr> | |||
</table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kj/3kjf_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3kjf ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Because of their central role in programmed cell death, the caspases are attractive targets for developing new therapeutics against cancer and autoimmunity, myocardial infarction and ischemic damage, and neurodegenerative diseases. We chose to target caspase-3, an executioner caspase, and caspase-8, an initiator caspase, based on the vast amount of information linking their functions to diseases. Through a structure-based drug design approach, a number of novel beta-strand peptidomimetic compounds were synthesized. Kinetic studies of caspase-3 and caspase-8 inhibition were carried out with these urazole ring-containing irreversible peptidomimetics and a known irreversible caspase inhibitor, Z-VAD-fmk. Using a stopped-flow fluorescence assay, we were able to determine individual kinetic parameters of caspase-3 and caspase-8 inhibition by these inhibitors. Z-VAD-fmk and the peptidomimetic inhibitors inhibit caspase-3 and caspase-8 via a three-step kinetic mechanism. Inhibition of both caspase-3 and caspase-8 by Z-VAD-fmk and of caspase-3 by the peptidomimetic inhibitors proceeds via two rapid equilibrium steps followed by a relatively fast inactivation step. However, caspase-8 inhibition by the peptidomimetics goes through a rapid equilibrium step, a slow-binding reversible step, and an extremely slow inactivation step. The crystal structures of inhibitor complexes of caspases-3 and -8 validate the design of the inhibitors by illustrating in detail how they mimic peptide substrates. One of the caspase-8 structures also shows binding at a secondary, allosteric site, providing a possible route to the development of noncovalent small molecule modulators of caspase activity. | |||
Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors.,Wang Z, Watt W, Brooks NA, Harris MS, Urban J, Boatman D, McMillan M, Kahn M, Heinrikson RL, Finzel BC, Wittwer AJ, Blinn J, Kamtekar S, Tomasselli AG Biochim Biophys Acta. 2010 Sep;1804(9):1817-1831. Epub 2010 May 24. PMID:20580860<ref>PMID:20580860</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3kjf" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Caspase|Caspase]] | *[[Caspase 3D structures|Caspase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Blinn | [[Category: Large Structures]] | ||
[[Category: Finzel | [[Category: Blinn J]] | ||
[[Category: Harris | [[Category: Finzel BC]] | ||
[[Category: Kamtekar | [[Category: Harris MS]] | ||
[[Category: Tomasselli | [[Category: Kamtekar S]] | ||
[[Category: Wang | [[Category: Tomasselli AG]] | ||
[[Category: Watt | [[Category: Wang Z]] | ||
[[Category: Watt W]] | |||