NDLI: Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against “Nucleotide-competing Reverse Transcriptase Inhibitors”*

Content Provider	PubMed Central
Author	Ehteshami, Maryam Scarth, Brian J. Tchesnokov, Egor P. Dash, Chandravanu Grice, Stuart F. J. Le Hallenberger, Sabine Dirk, Jochmans Matthias, Götte
Abstract	Indolopyridones are potent inhibitors of reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1). Although the structure of these compounds differs from established nucleoside analogue RT inhibitors (NRTIs), previous studies suggest that the prototype compound INDOPY-1 may bind in close proximity to the polymerase active site. NRTI-associated mutations that are clustered around the active site confer decreased, e.g. M184V and Y115F, or increased, e.g. K65R, susceptibility to INDOPY-1. Here we have studied the underlying biochemical mechanism. RT enzymes containing the isolated mutations M184V and Y115F cause 2–3-fold increases in IC50 values, while the combination of the two mutations causes a >15-fold increase. K65R can partially counteract these effects. Binding studies revealed that the M184V change reduces the affinity to INDOPY-1, while Y115F facilitates binding of the natural nucleotide substrate and the combined effects enhance the ability of the enzyme to discriminate against the inhibitor. Studies with other strategic mutations at residues Phe-61 and Ala-62, as well as the use of chemically modified templates shed further light on the putative binding site of the inhibitor and ternary complex formation. An abasic site residue at position n, i.e. opposite the 3′-end of the primer, prevents binding of INDOPY-1, while an abasic site at the adjacent position n+1 has no effect. Collectively, our findings provide strong evidence to suggest that INDOPY-1 can compete with natural deoxynucleoside triphosphates (dNTPs). We therefore propose to refer to members of this class of compounds as “nucleotide-competing RT inhibitors” (NcRTIs).
Related Links	http://dx.doi.org/10.1074/jbc.m804882200
Ending Page	29911
Page Count	8
Starting Page	29904
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	44
Volume Number	283
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2008-10-31
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against “Nucleotide-competing Reverse Transcriptase Inhibitors”

Mutations M184V and Y115F in HIV-1 reverse transcriptase discriminate against 'nucleotide-competing reverse transcriptase inhibitors'.

Formation of a Quaternary Complex of HIV-1 Reverse Transcriptase with a Nucleotide-competing Inhibitor and Its ATP Enhancer*

Mechanistic Basis for Reduced Viral and Enzymatic Fitness of HIV-1 Reverse Transcriptase Containing Both K65R and M184V Mutations

Formation of a quaternary complex of HIV-1 reverse transcriptase with a nucleotide-competing inhibitor and its ATP enhancer.

Formation of a Quaternary Complex of HIV-1 Reverse Transcriptase with a Nucleotide-competing Inhibitor and Its ATP Enhancer

HIV-1 Reverse Transcriptase (RT) Polymorphism 172K Suppresses the Effect of Clinically Relevant Drug Resistance Mutations to Both Nucleoside and Non-nucleoside RT Inhibitors*

Specific HIV-1 Reverse Transcriptase Inhibitors

EFFECT OF TRANSLOCATION DEFECTIVE REVERSE TRANSCRIPTASE INHIBITORS ON THE ACTIVITY OF N348I, A CONNECTION SUBDOMAIN DRUG RESISTANT HIV-1 REVERSE TRANSCRIPTASE MUTANT

Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against “Nucleotide-competing Reverse Transcriptase Inhibitors”*

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Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against “Nucleotide-competing Reverse Transcriptase Inhibitors”

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Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against “Nucleotide-competing Reverse Transcriptase Inhibitors”*