↓ Skip to main content

The mechanism of H171T resistance reveals the importance of Nδ-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase

Overview of attention for article published in Retrovirology, November 2014
Altmetric Badge

About this Attention Score

  • Average Attention Score compared to outputs of the same age

Mentioned by

twitter
2 X users

Citations

dimensions_citation
39 Dimensions

Readers on

mendeley
30 Mendeley
You are seeing a free-to-access but limited selection of the activity Altmetric has collected about this research output. Click here to find out more.
Title
The mechanism of H171T resistance reveals the importance of Nδ-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase
Published in
Retrovirology, November 2014
DOI 10.1186/s12977-014-0100-1
Pubmed ID
Authors

Alison Slaughter, Kellie A Jurado, Nanjie Deng, Lei Feng, Jacques J Kessl, Nikoloz Shkriabai, Ross C Larue, Hind J Fadel, Pratiq A Patel, Nivedita Jena, James R Fuchs, Eric Poeschla, Ronald M Levy, Alan Engelman, Mamuka Kvaratskhelia

Abstract

BackgroundAllosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an important new class of anti-HIV-1 agents. ALLINIs bind at the IN catalytic core domain (CCD) dimer interface occupying the principal binding pocket of its cellular cofactor LEDGF/p75. Consequently, ALLINIs inhibit HIV-1 IN interaction with LEDGF/p75 as well as promote aberrant IN multimerization. Selection of viral strains emerging under the inhibitor pressure has revealed mutations at the IN dimer interface near the inhibitor binding site.ResultsWe have investigated the effects of one of the most prevalent substitutions, H171T IN, selected under increasing pressure of ALLINI BI-D. Virus containing the H171T IN substitution exhibited an ~68-fold resistance to BI-D treatment in infected cells. These results correlated with ~84-fold reduced affinity for BI-D binding to recombinant H171T IN CCD protein compared to its wild type (WT) counterpart. However, the H171T IN substitution only modestly affected IN-LEDGF/p75 binding and allowed HIV-1 containing this substitution to replicate at near WT levels. The x-ray crystal structures of BI-D binding to WT and H171T IN CCD dimers coupled with binding free energy calculations revealed the importance of the N¿- protonated imidazole group of His171 for hydrogen bonding to the BI-D tert-butoxy ether oxygen and establishing electrostatic interactions with the inhibitor carboxylic acid, whereas these interactions were compromised upon substitution to Thr171.ConclusionsOur findings reveal a distinct mechanism of resistance for the H171T IN mutation to ALLINI BI-D and indicate a previously undescribed role of the His171 side chain for binding the inhibitor.

X Demographics

X Demographics

The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 30 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Netherlands 1 3%
Unknown 29 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 8 27%
Researcher 6 20%
Student > Master 3 10%
Student > Doctoral Student 2 7%
Student > Bachelor 1 3%
Other 2 7%
Unknown 8 27%
Readers by discipline Count As %
Immunology and Microbiology 6 20%
Chemistry 5 17%
Agricultural and Biological Sciences 5 17%
Biochemistry, Genetics and Molecular Biology 4 13%
Physics and Astronomy 1 3%
Other 1 3%
Unknown 8 27%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 October 2015.
All research outputs
#15,866,607
of 23,577,654 outputs
Outputs from Retrovirology
#791
of 1,118 outputs
Outputs of similar age
#218,361
of 365,653 outputs
Outputs of similar age from Retrovirology
#12
of 19 outputs
Altmetric has tracked 23,577,654 research outputs across all sources so far. This one is in the 22nd percentile – i.e., 22% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,118 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.1. This one is in the 17th percentile – i.e., 17% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 365,653 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 31st percentile – i.e., 31% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 19 others from the same source and published within six weeks on either side of this one. This one is in the 10th percentile – i.e., 10% of its contemporaries scored the same or lower than it.