Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target

ABSTRACT E165R, a highly specific dUTP nucleotidohydrolase (dUTPase) encoded by the African swine fever virus (ASFV) genome, is required for productive replication of ASFV in swine macrophages. Here, we solved the high-resolution crystal structures of E165R in its apo state and in complex with its p...

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Autores principales:	Changyao Li, Yan Chai, Hao Song, Changjiang Weng, Jianxun Qi, Yeping Sun, George F. Gao
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	African swine fever virus dUTPase E165R crystal structure drug target Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6b523e27dad8474bacd1723466769527
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spelling	oai:doaj.org-article:6b523e27dad8474bacd17234667695272021-11-15T15:59:41ZCrystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target10.1128/mBio.02483-192150-7511https://doaj.org/article/6b523e27dad8474bacd17234667695272019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02483-19https://doaj.org/toc/2150-7511ABSTRACT E165R, a highly specific dUTP nucleotidohydrolase (dUTPase) encoded by the African swine fever virus (ASFV) genome, is required for productive replication of ASFV in swine macrophages. Here, we solved the high-resolution crystal structures of E165R in its apo state and in complex with its product dUMP. Structural analysis explicitly defined the architecture of the active site of the enzyme as well as the interaction between the active site and the dUMP ligand. By comparing the ASFV E165R structure with dUTPase structures from other species, we found that the active site of E165R is highly similar to those of dUTPases from Mycobacterium tuberculosis and Plasmodium falciparum, against which small-molecule chemicals have been developed, which could be the potential drug or lead compound candidates for ASFV. Our results provide important basis for anti-ASFV drug design by targeting E165R. IMPORTANCE African swine fever virus (ASFV), an Asfivirus affecting pigs and wild boars with up to 100% case fatality rate, is currently rampaging throughout China and some other countries in Asia. There is an urgent need to develop therapeutic and preventive reagents against the virus. Our crystallographic and biochemical studies reveal that ASFV E165R is a member of trimeric dUTP nucleotidohydrolase (dUTPase) family that catalyzes the hydrolysis of dUTP into dUMP. Our apo-E165R and E165R-dUMP structures reveal the constitutive residues and the configuration of the active center of this enzyme in rich detail and give evidence that the active center of E165R is very similar to that of dUTPases from Plasmodium falciparum and Mycobacterium tuberculosis, which have already been used as targets for designing drugs. Therefore, our high-resolution structures of E165R provide useful structural information for chemotherapeutic drug design.Changyao LiYan ChaiHao SongChangjiang WengJianxun QiYeping SunGeorge F. GaoAmerican Society for MicrobiologyarticleAfrican swine fever virusdUTPaseE165Rcrystal structuredrug targetMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	African swine fever virus dUTPase E165R crystal structure drug target Microbiology QR1-502
spellingShingle	African swine fever virus dUTPase E165R crystal structure drug target Microbiology QR1-502 Changyao Li Yan Chai Hao Song Changjiang Weng Jianxun Qi Yeping Sun George F. Gao Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target
description	ABSTRACT E165R, a highly specific dUTP nucleotidohydrolase (dUTPase) encoded by the African swine fever virus (ASFV) genome, is required for productive replication of ASFV in swine macrophages. Here, we solved the high-resolution crystal structures of E165R in its apo state and in complex with its product dUMP. Structural analysis explicitly defined the architecture of the active site of the enzyme as well as the interaction between the active site and the dUMP ligand. By comparing the ASFV E165R structure with dUTPase structures from other species, we found that the active site of E165R is highly similar to those of dUTPases from Mycobacterium tuberculosis and Plasmodium falciparum, against which small-molecule chemicals have been developed, which could be the potential drug or lead compound candidates for ASFV. Our results provide important basis for anti-ASFV drug design by targeting E165R. IMPORTANCE African swine fever virus (ASFV), an Asfivirus affecting pigs and wild boars with up to 100% case fatality rate, is currently rampaging throughout China and some other countries in Asia. There is an urgent need to develop therapeutic and preventive reagents against the virus. Our crystallographic and biochemical studies reveal that ASFV E165R is a member of trimeric dUTP nucleotidohydrolase (dUTPase) family that catalyzes the hydrolysis of dUTP into dUMP. Our apo-E165R and E165R-dUMP structures reveal the constitutive residues and the configuration of the active center of this enzyme in rich detail and give evidence that the active center of E165R is very similar to that of dUTPases from Plasmodium falciparum and Mycobacterium tuberculosis, which have already been used as targets for designing drugs. Therefore, our high-resolution structures of E165R provide useful structural information for chemotherapeutic drug design.
format	article
author	Changyao Li Yan Chai Hao Song Changjiang Weng Jianxun Qi Yeping Sun George F. Gao
author_facet	Changyao Li Yan Chai Hao Song Changjiang Weng Jianxun Qi Yeping Sun George F. Gao
author_sort	Changyao Li
title	Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target
title_short	Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target
title_full	Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target
title_fullStr	Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target
title_full_unstemmed	Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target
title_sort	crystal structure of african swine fever virus dutpase reveals a potential drug target
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/6b523e27dad8474bacd1723466769527
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_version_	1718426972020801536

Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target

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