3OYJ

Crystal structure of the PFV S217Q mutant intasome in complex with magnesium and the INSTI MK2048

Summary for 3OYJ

• Entry DOI: 10.2210/pdb3oyj/pdb
• Related: 3DLR 3L2Q 3L2R 3L2U 3L2V 3L2W 3OY9 3OYA 3OYB 3OYC 3OYD 3OYE 3OYF 3OYG 3OYH 3OYI 3OYJ 3OYK 3OYL 3OYM 3OYN
• Descriptor: PFV integrase, DNA (5'-D(*AP*TP*TP*GP*TP*CP*AP*TP*GP*GP*AP*AP*TP*TP*TP*CP*GP*CP*A)-3'), DNA (5'-D(*TP*GP*CP*GP*AP*AP*AP*TP*TP*CP*CP*AP*TP*GP*AP*CP*A)-3'), ... (10 entities in total)
• Functional Keywords: protein-dna complex, tetramer, dna integration, endonuclease, metal-binding, multifunctional enzyme, nuclease, nucleotidyltransferase, nucleus, transferase, viral nucleoprotein, virion, dna-binding, zinc binding, hhcc motif, viral protein, recombination, inhibitor, dna-binding protein-dna complex, viral protein-dna complex, viral protein/dna
• Biological source: Human spumaretrovirus (SFVcpz(hu)); More
• Cellular location: Integrase: Virion (Potential). Protease/Reverse transcriptase/ribonuclease H: Host nucleus (By similarity): P14350
• Total number of polymer chains: 4
• Total formula weight: 101204.41

Authors

Hare, S.,Cherepanov, P. (deposition date: 2010-09-23, release date: 2010-11-17, Last modification date: 2023-09-06)

Primary citation

Hare, S.,Vos, A.M.,Clayton, R.F.,Thuring, J.W.,Cummings, M.D.,Cherepanov, P.
Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance.
Proc.Natl.Acad.Sci.USA, 107:20057-20062, 2010

PubMed Abstract: The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding of viral resistance to these molecules have been hampered by a paucity of available structural data. We recently reported cocrystal structures of the prototype foamy virus (PFV) intasome with raltegravir and elvitegravir, establishing the general INSTI binding mode. We now present an expanded set of cocrystal structures containing PFV intasomes complexed with first- and second-generation INSTIs at resolutions of up to 2.5 Å. Importantly, the improved resolution allowed us to refine the complete coordination spheres of the catalytic metal cations within the INSTI-bound intasome active site. We show that like the Q148H/G140S and N155H HIV-1 IN variants, the analogous S217H and N224H PFV INs display reduced sensitivity to raltegravir in vitro. Crystal structures of the mutant PFV intasomes in INSTI-free and -bound forms revealed that the amino acid substitutions necessitate considerable conformational rearrangements within the IN active site to accommodate an INSTI, thus explaining their adverse effects on raltegravir antiviral activity. Furthermore, our structures predict physical proximity and an interaction between HIV-1 IN mutant residues His148 and Ser/Ala140, rationalizing the coevolution of Q148H and G140S/A mutations in drug-resistant viral strains.

PubMed: 21030679
DOI: 10.1073/pnas.1010246107

Experimental method

X-RAY DIFFRACTION (2.68 Å)