Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening.
HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs.
Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, United States.
Joseph D
JD
Bauman
Disha
D
Patel
Chhaya
C
Dharia
Marc W
MW
Fromer
Sameer
S
Ahmed
Yulia
Y
Frenkel
R S K
RS
Vijayan
J Thomas
JT
Eck
William C
WC
Ho
Kalyan
K
Das
Aaron J
AJ
Shatkin
Eddy
E
Arnold
D000495:Allosteric Site; D001483:Base Sequence; D018360:Crystallography, X-Ray; D017931:DNA Primers; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation
D017931:DNA Primers; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase