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Antimicrob Agents Chemother. 2016 Aug 22;60(9):5608-11. doi: 10.1128/AAC.00976-16. Print 2016 Sep.

The DNA Polymerase Gamma R953C Mutant Is Associated with Antiretroviral Therapy-Induced Mitochondrial Toxicity.

Author information

1
Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
2
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
3
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
4
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA ywyin@utmb.edu karen.anderson@yale.edu elijah.paintsil@yale.edu.
5
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA ywyin@utmb.edu karen.anderson@yale.edu elijah.paintsil@yale.edu.
6
Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA Department of Epidemiology & Public Health, Yale School of Medicine, New Haven, Connecticut, USA ywyin@utmb.edu karen.anderson@yale.edu elijah.paintsil@yale.edu.

Abstract

We found a heterozygous C2857T mutation (R953C) in polymerase gamma (Pol-γ) in an HIV-infected patient with mitochondrial toxicity. The R953C Pol-γ mutant binding affinity for dCTP is 8-fold less than that of the wild type. The R953C mutant shows a 4-fold decrease in discrimination of analog nucleotides relative to the wild type. R953 is located on the "O-helix" that forms the substrate deoxynucleoside triphosphate (dNTP) binding site; the interactions of R953 with E1056 and Y986 may stabilize the O-helix and affect polymerase activity.

PMID:
27381400
PMCID:
PMC4997837
[Available on 2017-03-01]
DOI:
10.1128/AAC.00976-16
[Indexed for MEDLINE]
Free PMC Article

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