3KK1

HIV-1 reverse transcriptase-DNA complex with nuceotide inhibitor GS-9148-diphosphate bound in nucleotide site

Summary for 3KK1

• Entry DOI: 10.2210/pdb3kk1/pdb
• Related: 3kjv 3kk2 3kk3
• Descriptor: Reverse transcriptase p66 subunit, Reverse transcriptase p51 subunit, 5'-D(*AP*CP*A*GP*TP*CP*CP*CP*TP*GP*TP*TP*CP*GP*GP*GP*CP*GP*CP*CP*(DOC))-3', ... (8 entities in total)
• Functional Keywords: hiv, reverse transcriptase, protein-dna complex, transferase-dna complex, transferase/dna
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04585 P04585
• Total number of polymer chains: 4
• Total formula weight: 132881.78

Authors

Lansdon, E.B. (deposition date: 2009-11-04, release date: 2010-03-23, Last modification date: 2023-09-06)

Primary citation

Lansdon, E.B.,Samuel, D.,Lagpacan, L.,Brendza, K.M.,White, K.L.,Hung, M.,Liu, X.,Boojamra, C.G.,Mackman, R.L.,Cihlar, T.,Ray, A.S.,McGrath, M.E.,Swaminathan, S.
Visualizing the molecular interactions of a nucleotide analog, GS-9148, with HIV-1 reverse transcriptase-DNA complex.
J.Mol.Biol., 397:967-978, 2010

PubMed Abstract: GS-9148 ([5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid) is a dAMP (2'-deoxyadenosine monophosphate) analog that maintains its antiviral activity against drug-resistant HIV. Crystal structures for HIV-1 reverse transcriptase (RT) bound to double-stranded DNA, ternary complexes with either GS-9148-diphosphate or 2'-deoxyadenosine triphosphate (dATP), and a post-incorporation structure with GS-9148 translocated to the priming site were obtained to gain insight into the mechanism of RT inhibition. The binding of either GS-9148-diphosphate or dATP to the binary RT-DNA complex resulted in the fingers subdomain closing around the incoming substrate. This produced up to a 9 A shift in the tips of the fingers subdomain as it closed toward the palm and thumb subdomains. GS-9148-diphosphate shows a similar binding mode as dATP in the nucleotide-binding site. Residues whose mutations confer resistance to nucleotide/nucleoside RT inhibitors, such as M184, Y115, L74, and K65, show little to no shift in orientation whether GS-9148-diphosphate or dATP is bound. One difference observed in binding is the position of the central ring. The dihydrofuran ring of GS-9148-diphosphate interacts with the aromatic side chain of Y115 more than does the ribose ring of dATP, possibly picking up a favorable pi-pi interaction. The ability of GS-9148-diphosphate to mimic the active-site contacts of dATP may explain its effective inhibition of RT and maintained activity against resistance mutations. Interestingly, the 2'-fluoro moiety of GS-9148-diphosphate was found in close proximity to the Q151 side chain, potentially explaining the observed moderately reduced susceptibly to GS-9148 conferred by Q151M mutation.

PubMed: 20156454
DOI: 10.1016/j.jmb.2010.02.019

Experimental method

X-RAY DIFFRACTION (2.7 Å)