3OYN: Crystal Structure of the PFV N224h Mutant Intasome Bound to Magnesium and the Insti Mk2048

Citation:
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 A. 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.
PDB ID: 3OYNDownload
MMDB ID: 86325
PDB Deposition Date: 2010/9/23
Updated in MMDB: 2010/12 
Experimental Method:
x-ray diffraction
Resolution: 2.68  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 3OYN: octameric; determined by author and by software (PISA)
Molecular Components in 3OYN
Label Count Molecule
Proteins (4 molecules)
4
PFV Integrase
Molecule annotation
Nucleotides(2 molecules)
2
DNA (5'- D(*ap*tp*tp*gp*tp*cp*ap*tp*gp*gp*ap*ap*tp*tp*tp*cp*gp*cp*a)-3')
Molecule annotation
2
DNA (5'- D(*tp*gp*cp*gp*ap*ap*ap*tp*tp*cp*cp*ap*tp*gp*ap*cp*a)-3')
Molecule annotation
Chemicals (24 molecules)
1
2
2
6
3
8
4
2
5
4
6
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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