Structural basis for the dual thymidine and thymidylate kinase activity of herpes thymidine kinases

Anna Gardberg; Ludmilla Shuvalova; Christian Monnerjahn; Manfred Konrad; Arnon Lavie

doi:10.1016/j.str.2003.09.003

Structural basis for the dual thymidine and thymidylate kinase activity of herpes thymidine kinases

Anna Gardberg, Ludmilla Shuvalova, Christian Monnerjahn, Manfred Konrad, Arnon Lavie^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Crystal structures of equine herpesvirus type-4 thymidine kinase (EHV4-TK) in complex with (i) thymidine and ADP, (ii) thymidine and SO₄ and the bisubstrate analogs, (iii) TP₄A, and (iv) TP₅A have been solved. Additionally, the structure of herpes simplex virus type-1 thymidine kinase (HSV1-TK) in complex with TP₅A has been determined. These are the first structures of nucleoside kinases revealing conformational transitions upon binding of bisubstrate analogs. The structural basis for the dual thymidine and thymidylate kinase activity of these TKs is elucidated. While the active sites of HSV1-TK and EHV4-TK resemble one another, notable differences are observed in the Lid regions and in the way the enzymes bind the base of the phosphoryl-acceptor. The latter difference could partly explain the higher activity of EHV4-TK toward the prodrug ganciclovir.

Original language	English (US)
Pages (from-to)	1265-1277
Number of pages	13
Journal	Structure
Volume	11
Issue number	10
DOIs	https://doi.org/10.1016/j.str.2003.09.003
State	Published - Oct 1 2003

Funding

A.S.G. and A.L. are supported by a grant from the National Science Foundation. C.M. and M.K. are supported by the Deutsche Forschungsgemeinschaft and the Max-Planck-Gesellschaft. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. Use of the BioCARS Sector 14 was supported by the National Institutes of Health, National Center for Research Resources, under grant number RR07707.

ASJC Scopus subject areas

Molecular Biology
Structural Biology

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title = "Structural basis for the dual thymidine and thymidylate kinase activity of herpes thymidine kinases",

abstract = "Crystal structures of equine herpesvirus type-4 thymidine kinase (EHV4-TK) in complex with (i) thymidine and ADP, (ii) thymidine and SO4 and the bisubstrate analogs, (iii) TP4A, and (iv) TP5A have been solved. Additionally, the structure of herpes simplex virus type-1 thymidine kinase (HSV1-TK) in complex with TP5A has been determined. These are the first structures of nucleoside kinases revealing conformational transitions upon binding of bisubstrate analogs. The structural basis for the dual thymidine and thymidylate kinase activity of these TKs is elucidated. While the active sites of HSV1-TK and EHV4-TK resemble one another, notable differences are observed in the Lid regions and in the way the enzymes bind the base of the phosphoryl-acceptor. The latter difference could partly explain the higher activity of EHV4-TK toward the prodrug ganciclovir.",

author = "Anna Gardberg and Ludmilla Shuvalova and Christian Monnerjahn and Manfred Konrad and Arnon Lavie",

note = "Funding Information: A.S.G. and A.L. are supported by a grant from the National Science Foundation. C.M. and M.K. are supported by the Deutsche Forschungsgemeinschaft and the Max-Planck-Gesellschaft. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. Use of the BioCARS Sector 14 was supported by the National Institutes of Health, National Center for Research Resources, under grant number RR07707. ",

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AU - Shuvalova, Ludmilla

AU - Monnerjahn, Christian

AU - Konrad, Manfred

AU - Lavie, Arnon

N1 - Funding Information: A.S.G. and A.L. are supported by a grant from the National Science Foundation. C.M. and M.K. are supported by the Deutsche Forschungsgemeinschaft and the Max-Planck-Gesellschaft. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. Use of the BioCARS Sector 14 was supported by the National Institutes of Health, National Center for Research Resources, under grant number RR07707.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - Crystal structures of equine herpesvirus type-4 thymidine kinase (EHV4-TK) in complex with (i) thymidine and ADP, (ii) thymidine and SO4 and the bisubstrate analogs, (iii) TP4A, and (iv) TP5A have been solved. Additionally, the structure of herpes simplex virus type-1 thymidine kinase (HSV1-TK) in complex with TP5A has been determined. These are the first structures of nucleoside kinases revealing conformational transitions upon binding of bisubstrate analogs. The structural basis for the dual thymidine and thymidylate kinase activity of these TKs is elucidated. While the active sites of HSV1-TK and EHV4-TK resemble one another, notable differences are observed in the Lid regions and in the way the enzymes bind the base of the phosphoryl-acceptor. The latter difference could partly explain the higher activity of EHV4-TK toward the prodrug ganciclovir.

AB - Crystal structures of equine herpesvirus type-4 thymidine kinase (EHV4-TK) in complex with (i) thymidine and ADP, (ii) thymidine and SO4 and the bisubstrate analogs, (iii) TP4A, and (iv) TP5A have been solved. Additionally, the structure of herpes simplex virus type-1 thymidine kinase (HSV1-TK) in complex with TP5A has been determined. These are the first structures of nucleoside kinases revealing conformational transitions upon binding of bisubstrate analogs. The structural basis for the dual thymidine and thymidylate kinase activity of these TKs is elucidated. While the active sites of HSV1-TK and EHV4-TK resemble one another, notable differences are observed in the Lid regions and in the way the enzymes bind the base of the phosphoryl-acceptor. The latter difference could partly explain the higher activity of EHV4-TK toward the prodrug ganciclovir.

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Structural basis for the dual thymidine and thymidylate kinase activity of herpes thymidine kinases

Abstract

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