Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.

During the glyoxylate cycle, isocitrate lyases (ICLs) catalyze the lysis of isocitrate to glyoxylate and succinate. Itaconate has been reported to inhibit an ICL from Mycobacterium tuberculosis (tbICL). To elucidate the molecular mechanism of ICL inhibition, we determined the crystal structure of tb...

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Autores principales:	Sunghark Kwon, Hye Lin Chun, Hyun Ji Ha, So Yeon Lee, Hyun Ho Park
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9c4e927bbb4e42e8914e0d36f6ee0848
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spelling	oai:doaj.org-article:9c4e927bbb4e42e8914e0d36f6ee08482021-11-25T05:54:19ZHeterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.1932-620310.1371/journal.pone.0251067https://doaj.org/article/9c4e927bbb4e42e8914e0d36f6ee08482021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0251067https://doaj.org/toc/1932-6203During the glyoxylate cycle, isocitrate lyases (ICLs) catalyze the lysis of isocitrate to glyoxylate and succinate. Itaconate has been reported to inhibit an ICL from Mycobacterium tuberculosis (tbICL). To elucidate the molecular mechanism of ICL inhibition, we determined the crystal structure of tbICL in complex with itaconate. Unexpectedly, succinate and itaconate were found to bind to the respective active sites in the dimeric form of tbICL. Our structure revealed the active site architecture as an open form, although the substrate and inhibitor were bound to the active sites. Our findings provide novel insights into the conformation of tbICL upon its binding to a substrate or inhibitor, along with molecular details of the inhibitory mechanism of itaconate.Sunghark KwonHye Lin ChunHyun Ji HaSo Yeon LeeHyun Ho ParkPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 5, p e0251067 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sunghark Kwon Hye Lin Chun Hyun Ji Ha So Yeon Lee Hyun Ho Park Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.
description	During the glyoxylate cycle, isocitrate lyases (ICLs) catalyze the lysis of isocitrate to glyoxylate and succinate. Itaconate has been reported to inhibit an ICL from Mycobacterium tuberculosis (tbICL). To elucidate the molecular mechanism of ICL inhibition, we determined the crystal structure of tbICL in complex with itaconate. Unexpectedly, succinate and itaconate were found to bind to the respective active sites in the dimeric form of tbICL. Our structure revealed the active site architecture as an open form, although the substrate and inhibitor were bound to the active sites. Our findings provide novel insights into the conformation of tbICL upon its binding to a substrate or inhibitor, along with molecular details of the inhibitory mechanism of itaconate.
format	article
author	Sunghark Kwon Hye Lin Chun Hyun Ji Ha So Yeon Lee Hyun Ho Park
author_facet	Sunghark Kwon Hye Lin Chun Hyun Ji Ha So Yeon Lee Hyun Ho Park
author_sort	Sunghark Kwon
title	Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.
title_short	Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.
title_full	Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.
title_fullStr	Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.
title_full_unstemmed	Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.
title_sort	heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/9c4e927bbb4e42e8914e0d36f6ee0848
work_keys_str_mv	AT sungharkkwon heterogeneousmultimericstructureofisocitratelyaseincomplexwithsuccinateanditaconateprovidesnovelinsightsintoitsinhibitorymechanism AT hyelinchun heterogeneousmultimericstructureofisocitratelyaseincomplexwithsuccinateanditaconateprovidesnovelinsightsintoitsinhibitorymechanism AT hyunjiha heterogeneousmultimericstructureofisocitratelyaseincomplexwithsuccinateanditaconateprovidesnovelinsightsintoitsinhibitorymechanism AT soyeonlee heterogeneousmultimericstructureofisocitratelyaseincomplexwithsuccinateanditaconateprovidesnovelinsightsintoitsinhibitorymechanism AT hyunhopark heterogeneousmultimericstructureofisocitratelyaseincomplexwithsuccinateanditaconateprovidesnovelinsightsintoitsinhibitorymechanism
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Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism.

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