6px9

From Proteopedia

(Difference between revisions)

Revision as of 07:14, 4 March 2020

Crystal structure of procaspase-8 in complex with covalent small molecule inhibitor 63-R

Structural highlights

6px9 is a 6 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:	CASP8, MCH5 (HUMAN)
Activity:	Caspase-8, with EC number 3.4.22.61
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CASP8_HUMAN] Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.^[1]

Function

[CASP8_HUMAN] Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.^[2] ^[3]

Publication Abstract from PubMed

Caspases are a critical class of proteases involved in regulating programmed cell death and other biological processes. Selective inhibitors of individual caspases, however, are lacking, due in large part to the high structural similarity found in the active sites of these enzymes. We recently discovered a small-molecule inhibitor, 63-R, that covalently binds the zymogen, or inactive precursor (pro-form), of caspase-8, but not other caspases, pointing to an untapped potential of procaspases as targets for chemical probes. Realizing this goal would benefit from a structural understanding of how small molecules bind to and inhibit caspase zymogens. There have, however, been very few reported procaspase structures. Here, we employ X-ray crystallography to elucidate a procaspase-8 crystal structure in complex with 63-R, which reveals large conformational changes in active-site loops that accommodate the intramolecular cleavage events required for protease activation. Combining these structural insights with molecular modeling and mutagenesis-based biochemical assays, we elucidate key interactions required for 63-R inhibition of procaspase-8. Our findings inform the mechanism of caspase activation and its disruption by small molecules and, more generally, have implications for the development of small molecule inhibitors and/or activators that target alternative (e.g., inactive precursor) protein states to ultimately expand the druggable proteome.

Integrative X-ray Structure and Molecular Modeling for the Rationalization of Procaspase-8 Inhibitor Potency and Selectivity.,Xu JH, Eberhardt J, Hill-Payne B, Gonzalez-Paez GE, Castellon JO, Cravatt BF, Forli S, Wolan DW, Backus KM ACS Chem Biol. 2020 Jan 23. doi: 10.1021/acschembio.0c00019. PMID:31927936^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002 Sep 26;419(6905):395-9. PMID:12353035 doi:10.1038/nature01063
↑ Himeji D, Horiuchi T, Tsukamoto H, Hayashi K, Watanabe T, Harada M. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood. 2002 Jun 1;99(11):4070-8. PMID:12010809
↑ Muzio M, Salvesen GS, Dixit VM. FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. J Biol Chem. 1997 Jan 31;272(5):2952-6. PMID:9006941
↑ Xu JH, Eberhardt J, Hill-Payne B, Gonzalez-Paez GE, Castellon JO, Cravatt BF, Forli S, Wolan DW, Backus KM. Integrative X-ray Structure and Molecular Modeling for the Rationalization of Procaspase-8 Inhibitor Potency and Selectivity. ACS Chem Biol. 2020 Jan 23. doi: 10.1021/acschembio.0c00019. PMID:31927936 doi:http://dx.doi.org/10.1021/acschembio.0c00019

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/6px9"

@@ Line 3: / Line 3: @@
 <StructureSection load='6px9' size='340' side='right'caption='[[6px9]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6px9]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PX9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PX9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6px9]] is a 6 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=6PX9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PX9 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=63R:N-{(3R)-1-[4-(morpholin-4-yl)benzene-1-carbonyl]piperidin-3-yl}-N-phenylacetamide'>63R</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP8, MCH5 ([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/Caspase-8 Caspase-8], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.61 3.4.22.61] </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=6px9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6px9 OCA], [http://pdbe.org/6px9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6px9 RCSB], [http://www.ebi.ac.uk/pdbsum/6px9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6px9 ProSAT]</span></td></tr>
@@ Line 26: / Line 27: @@
 </StructureSection>
 [[Category: Caspase-8]]
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Wolan, D W]]

6px9

From Proteopedia

Revision as of 07:14, 4 March 2020

Crystal structure of procaspase-8 in complex with covalent small molecule inhibitor 63-R

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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