Murine leukemia virus reverse transcriptase: Structural comparison with HIV-1 reverse transcriptase

Abstract

Recent X-ray crystal structure determinations of Moloney murine leukemia virus reverse transcriptase (MoMLV RT) have allowed for more accurate structure/function comparisons to HIV-1 RT than were formerly possible. Previous biochemical studies of MoMLV RT in conjunction with knowledge of sequence homologies to HIV-1 RT and overall fold similarities to RTs in general, provided a foundation upon which to build. In addition, numerous crystal structures of the MoMLV RT fingers/palm subdomain had also shed light on one of the critical functions of the enzyme, specifically polymerization. Now in the advent of new structural information, more intricate examination of MoMLV RT in its entirety can be realized, and thus the comparisons with HIV-1 RT may be more critically elucidated. Here, we will review the similarities and differences between MoMLV RT and HIV-1 RT via structural analysis, and propose working models for the MoMLV RT based upon that information.

Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase

“…Structural differences may also play a role in the observed decrease in RNase H activity for the gammaretroviral enzymes. Both the MoMLV and XMRV RTs exist as monomers, unlike the heterodimeric HIV-1 RT, which benefits from the additional support provided by the p51 subunit (17). An additional difference in nucleic acid binding includes the longer distance between the polymerase and RNase H active sites in XMRV RT than in HIV-1 RT (1 bp or approximately 3.4 Å) (28,76).…”

“…HIV-1 RT is structurally very different from the gammaretroviral MoMLV RT, which is closely related to XMRV RT in sequence and presumably in structure (17,28,29,61). HIV-1 RT exists as a heterodimer composed of two subunits: an enzymatically active 66-kDa p66 domain, which contains the polymerase domain (composed of the fingers, palm, thumb, and connection subdomains) and the RNase H domain, and a 51-kDa p51 domain, which mainly provides structural support and has an amino acid sequence identical to that of p66 but does not contain the RNase H domain, which is removed by proteolytic cleavage (38,45,72,75,79).…”

“…HIV-1 RT exists as a heterodimer composed of two subunits: an enzymatically active 66-kDa p66 domain, which contains the polymerase domain (composed of the fingers, palm, thumb, and connection subdomains) and the RNase H domain, and a 51-kDa p51 domain, which mainly provides structural support and has an amino acid sequence identical to that of p66 but does not contain the RNase H domain, which is removed by proteolytic cleavage (38,45,72,75,79). MoMLV RT is a 74-kDa monomer in the published crystal structures (17,18,29,60), lacking the structural support that p51 provides for HIV-1 RT. MoMLV RT may make up for this lack of structural support by possibly forming a homodimer during DNA synthesis (90).…”

Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening

“…In contrast, fragments 4, 5, and 8 and analogs 13 and 17 tended to have similar potency for HIV-1 and MoMLV RT. Although the sequence similarity between HIV-1 RT and MoMLV RT is low, ranging from 6% in the connection domain to 25% in the fingers and palm subdomains, both viral RTs have similar folding arrangements in their polymerase domains (31). The conformational landscape of the binding sites may therefore be very similar.…”

Reverse Transcriptase and Retroviral Replication

“…Structural analysis revealed that HIV-1 and MLV RTs are rather different at their thumb and connection subdomains, while their fingers and palm subdomains show significant homology (for a review, see Coté & Roth, 2008). MLV RT is 111 amino acids longer than the p66 subunit of HIV-1 RT.…”