Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target.
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.
['Li|Changyao|C|', 'Chai|Yan|Y|', 'Song|Hao|H|0000-0002-2811-0370', 'Weng|Changjiang|C|', 'Qi|Jianxun|J|0000-0002-9358-4732', 'Sun|Yeping|Y|', 'Gao|George F|GF|0000-0002-3869-615X']
D000357:African Swine Fever D000358:African Swine Fever Virus D000818:Animals D001665:Binding Sites D020134:Catalytic Domain D003001:Cloning, Molecular D018360:Crystallography, X-Ray D016503:Drug Delivery Systems D015195:Drug Design D007700:Kinetics D008958:Models, Molecular D009169:Mycobacterium tuberculosis D010963:Plasmodium falciparum D011487:Protein Conformation D011755:Pyrophosphatases D016415:Sequence Alignment D013552:Swine
crystal structure African swine fever virus dUTPase drug target E165R