3P1G

Crystal Structure of the Xenotropic Murine Leukemia Virus-Related Virus (XMRV) RNase H Domain

Summary for 3P1G

• Entry DOI: 10.2210/pdb3p1g/pdb
• Descriptor: Xenotropic Murine Leukemia Virus-Related Virus (XMRV) RNase H Domain, MAGNESIUM ION (3 entities in total)
• Functional Keywords: xmrv, rnase h, reverse transcriptase, transcription
• Biological source: Xenotropic MuLV-related virus
• Total number of polymer chains: 1
• Total formula weight: 17992.61

Authors

Kirby, K.A.,Sarafianos, S.G. (deposition date: 2010-09-30, release date: 2010-10-13, Last modification date: 2024-02-21)

Primary citation

Kirby, K.A.,Marchand, B.,Ong, Y.T.,Ndongwe, T.P.,Hachiya, A.,Michailidis, E.,Leslie, M.D.,Sietsema, D.V.,Fetterly, T.L.,Dorst, C.A.,Singh, K.,Wang, Z.,Parniak, M.A.,Sarafianos, S.G.
Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase.
Antimicrob.Agents Chemother., 56:2048-2061, 2012

PubMed Abstract: RNase H inhibitors (RNHIs) have gained attention as potential HIV-1 therapeutics. Although several RNHIs have been studied in the context of HIV-1 reverse transcriptase (RT) RNase H, there is no information on inhibitors that might affect the RNase H activity of other RTs. We performed biochemical, virological, crystallographic, and molecular modeling studies to compare the RNase H function and inhibition profiles of the gammaretroviral xenotropic murine leukemia virus-related virus (XMRV) and Moloney murine leukemia virus (MoMLV) RTs to those of HIV-1 RT. The RNase H activity of XMRV RT is significantly lower than that of HIV-1 RT and comparable to that of MoMLV RT. XMRV and MoMLV, but not HIV-1 RT, had optimal RNase H activities in the presence of Mn²⁺ and not Mg²⁺. Using hydroxyl-radical footprinting assays, we demonstrated that the distance between the polymerase and RNase H domains in the MoMLV and XMRV RTs is longer than that in the HIV-1 RT by ∼3.4 Å. We identified one naphthyridinone and one hydroxyisoquinolinedione as potent inhibitors of HIV-1 and XMRV RT RNases H with 50% inhibitory concentrations ranging from ∼0.8 to 0.02 μM. Two acylhydrazones effective against HIV-1 RT RNase H were less potent against the XMRV enzyme. We also solved the crystal structure of an XMRV RNase H fragment at high resolution (1.5 Å) and determined the molecular details of the XMRV RNase H active site, thus providing a framework that would be useful for the design of antivirals that target RNase H.

PubMed: 22252812
DOI: 10.1128/AAC.06000-11

Experimental method

X-RAY DIFFRACTION (1.5 Å)