About: Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch

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About: Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch Goto Sponge NotDistinct Permalink

An Entity of Type : http://linked.opendata.cz/ontology/domain/vavai/Vysledek, within Data Space : linked.opendata.cz associated with source document(s)

Attributes	Values
rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
rdfs:seeAlso	http://dx.doi.org/10.1016/j.str.2014.09.015
Description	Cathepsin B1 (SmCB1) is a digestive protease of the parasitic blood fluke Schistosoma mansoni and a drug target for the treatment of schistosomiasis, a disease that afflicts over 200 million people. SmCB1 is synthesized as an inactive zymogen in which the N-terminal propeptide blocks the active site. We investigated the activation of the zymogen by which the propeptide is proteolytically removed and its regulation by sulfated polysaccharides (SPs). We determined crystal structures of three molecular forms of SmCB1 along the activation pathway: the zymogen, an activation intermediate with a partially cleaved propeptide, and the mature enzyme. We demonstrate that SPs are essential for the autocatalytic activation of SmCB1, as they interact with a specific heparin-binding domain in the propeptide. An alternative activation route is mediated by an S. mansoni asparaginyl endopeptidase (legumain) which is downregulated by SPs, indicating that SPs act as a molecular switch between both activation mechanisms. Cathepsin B1 (SmCB1) is a digestive protease of the parasitic blood fluke Schistosoma mansoni and a drug target for the treatment of schistosomiasis, a disease that afflicts over 200 million people. SmCB1 is synthesized as an inactive zymogen in which the N-terminal propeptide blocks the active site. We investigated the activation of the zymogen by which the propeptide is proteolytically removed and its regulation by sulfated polysaccharides (SPs). We determined crystal structures of three molecular forms of SmCB1 along the activation pathway: the zymogen, an activation intermediate with a partially cleaved propeptide, and the mature enzyme. We demonstrate that SPs are essential for the autocatalytic activation of SmCB1, as they interact with a specific heparin-binding domain in the propeptide. An alternative activation route is mediated by an S. mansoni asparaginyl endopeptidase (legumain) which is downregulated by SPs, indicating that SPs act as a molecular switch between both activation mechanisms. (en)
Title	Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch (en)
skos:prefLabel	Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch Activation Route of the Schistosoma mansoni Cathepsin B1 Drug Target: Structural Map with a Glycosaminoglycan Switch (en)
skos:notation	RIV/00216208:11310/14:10289025!RIV15-MSM-11310___
http://linked.open...avai/riv/aktivita	I P S
http://linked.open...avai/riv/aktivity	I, P(GA203/09/1585), P(LH12023), P(LO1302), S
http://linked.open...iv/cisloPeriodika	12
http://linked.open...vai/riv/dodaniDat	2015
http://linked.open...aciTvurceVysledku	Jílková, Adéla
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Univerzita Karlova v Praze / Přírodovědecká fakulta
http://linked.open...dnocenehoVysledku	1515
http://linked.open...ai/riv/idVysledku	RIV/00216208:11310/14:10289025
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	expression; chemotherapy; ph; propeptide; cysteine proteases; hemoglobin digestion; in-vitro; asparaginyl endopeptidase; slow-binding inhibition; human procathepsin-b (en)
http://linked.open.../riv/klicoveSlovo	hemoglobin digestion propeptide expression chemotherapy in-vitro asparaginyl endopeptidase cysteine proteases human procathepsin-b ph slow-binding inhibition
http://linked.open...odStatuVydavatele	GB - Spojené království Velké Británie a Severního Irska
http://linked.open...ontrolniKodProRIV	[1E8609FB7DF3]
http://linked.open...i/riv/nazevZdroje	Structure
http://linked.open...in/vavai/riv/obor	CE
http://linked.open...ichTvurcuVysledku	1 (xsd:int)
http://linked.open...cetTvurcuVysledku	10 (xsd:int)
http://linked.open...vavai/riv/projekt	Novel antiparasite drugs: from target proteins to inhibitor chemotherapeutics Parasite-targeted peptidase inhibitors as a tool for schistosomiasis therapy. InterBioMed
http://linked.open...UplatneniVysledku	2014
http://linked.open...v/svazekPeriodika	22
http://linked.open...iv/tvurceVysledku	Brynda, Jiří Horn, Martin Mareš, Michael Vondrášek, Jiří Řezáčová, Pavlína Jílková, Adéla Marešová, Lucie Caffrey, Conor R. Fajtová, Pavla McKerrow, James H.
http://linked.open...ain/vavai/riv/wos	000345898700012
issn	0969-2126
number of pages	13 (xsd:int)
http://bibframe.org/vocab/doi	10.1016/j.str.2014.09.015
http://localhost/t...ganizacniJednotka	11310

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