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      Selective interactions between mimivirus uracil-DNA glycosylase and inhibitory proteins determined by a single amino acid.

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          Abstract

          Uracil-N-glycosylase (UNG) is found in most organisms as well as in large DNA viruses. Its inhibitory proteins, including uracil glycosylase inhibitor (UGI) and p56, tightly bind to the active site of UNG by mimicking the DNA substrates. As the binding motifs are conserved in UNG family proteins, the inhibitory proteins bind to various UNG proteins across species. However, the intercalation residue that penetrates the DNA minor groove during uracil excision is not conserved among UNG proteins. To understand the role of the intercalation residue in their binding to the inhibitory proteins, we prepared mutants of mimivirus UNG, measured the binding affinity between the UNG mutants and inhibitory proteins, and analyzed the interactions based on the crystal structures of mimivirus UNG mutants complexed with UGI. The results show that mimivirus UNG, which harbors Tyr as an intercalation residue, did not interact with the inhibitory proteins intrinsically, whereas mutations of the intercalation residue to Phe or Leu resulted in tight interactions with UGI and p56; mutation to Met resulted in tight interactions only with p56. The crystal structures revealed that Phe and Leu stabilize the interactions by fitting into the hydrophobic pocket of UGI. These results show that differences in size and hydrophobicity of the intercalation residues determine the interactions between UNG family proteins and the inhibitory proteins, UGI and p56.

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          Author and article information

          Journal
          J Struct Biol
          Journal of structural biology
          Elsevier BV
          1095-8657
          1047-8477
          September 01 2020
          : 211
          : 3
          Affiliations
          [1 ] College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, South Korea.
          [2 ] College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, South Korea. Electronic address: eunjukwon@ynu.ac.kr.
          [3 ] College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, South Korea. Electronic address: dyokim@ynu.ac.kr.
          Article
          S1047-8477(20)30125-8
          10.1016/j.jsb.2020.107552
          32569642
          6281cf5f-5048-4dd7-a34e-c49257efdde7
          Copyright © 2020 Elsevier Inc. All rights reserved.
          History

          Intercalation residue,Mimivirus,Uracil glycosylase inhibitor,uracil-N-glycosylase

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