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Effects of PRE and POST therapy drug‐pressure selected mutations on HIV‐1 protease conformational sampling
Author(s) -
Carter Jeffrey D.,
Gonzales Estrella G.,
Huang Xi,
Smith Adam N.,
de Vera Ian Mitchelle S.,
D'Amore Peter W.,
Rocca James R.,
Goodenow Maureen M.,
Dunn Ben M.,
Fanucci Gail E.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.06.051
Subject(s) - hiv 1 protease , protease , chemistry , mutant , conformational change , human immunodeficiency virus (hiv) , mutation , molecular dynamics , stereochemistry , biophysics , biochemistry , enzyme , biology , virology , computational chemistry , gene
Conformational sampling of pre‐ and post‐therapy subtype B HIV‐1 protease sequences derived from a pediatric subject infected via maternal transmission with HIV‐1 were characterized by double electron–electron resonance spectroscopy. The conformational ensemble of the PRE construct resembles native‐like inhibitor bound states. In contrast, the POST construct, which contains accumulated drug‐pressure selected mutations, has a predominantly semi‐open conformational ensemble, with increased populations of open‐like states. The single point mutant L63P, which is contained in PRE and POST, has decreased dynamics, particularly in the flap region, and also displays a closed‐like conformation of inhibitor‐bound states. These findings support our hypothesis that secondary mutations accumulate in HIV‐1 protease to shift conformational sampling to stabilize open‐like conformations, while maintaining the predominant semi‐open conformation for activity.