1fej
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STRUCTURAL IMPLICATIONS OF DRUG RESISTANT MUTANTS OF HIV-1 PROTEASE: HIGH RESOLUTION CRYSTAL STRUCTURES OF THE MUTANT PROTEASE/SUBSTRATE ANALOG COMPLEXES
OverviewOverview
Emergence of drug-resistant mutants of HIV-1 protease is an ongoing, problem in the fight against AIDS. The mechanisms governing resistance are, both complex and varied. We have determined crystal structures of HIV-1, protease mutants, D30N, K45I, N88D, and L90M complexed with peptide, inhibitor analogues of CA-p2 and p2-NC cleavage sites in the Gag-pol, precursor in order to study the structural mechanisms underlying, resistance. The structures were determined at 1.55-1.9-A resolution and, compared with the wild-type structure. The conformational disorder seen, for most of the hydrophobic side-chains around the inhibitor binding site, indicates flexibility of binding. Eight water molecules are conserved in, all 9 structures; their location suggests that they are important for, catalysis as well as structural stability. Structural differences among, the mutants were analyzed in relation to the observed changes in protease, activity and stability. Mutant L90M shows steric contacts with the, catalytic Asp25 that could destabilize the catalytic loop at the dimer, interface, leading to its observed decreased dimer stability and activity., Mutant K45I reduces the mobility of the flap and the inhibitor and, contributes to an enhancement in structural stability and activity. The, side-chain variations at residue 30 relative to wild-type are the largest, in D30N and the changes are consistent with the altered activity observed, with peptide substrates. Polar interactions in D30N are maintained, in, agreement with the observed urea sensitivity. The side-chains of D30N and, N88D are linked through a water molecule suggesting correlated changes at, the two sites, as seen with clinical inhibitors. Structural changes seen, in N88D are small; however, water molecules that mediate interactions, between Asn88 and Thr74/Thr31/Asp30 in other complexes are missing in, N88D.
About this StructureAbout this Structure
1FEJ is a Single protein structure of sequence from Human immunodeficiency virus 1 with ACE as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
ReferenceReference
Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes., Mahalingam B, Louis JM, Hung J, Harrison RW, Weber IT, Proteins. 2001 Jun 1;43(4):455-64. PMID:11340661
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