tailieunhanh - Báo cáo Y học: Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant

The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combinationtherapy. The drugs Efavirenz, MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT, including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and PNU142721 and MSC194 in complex with the K103N mutant. The structures unanimously indicate that the K103N substitution induces only minor positional adjustments of the three inhibitors and the residues. | Eur. J. Biochem. 269 1670-1677 2002 FEBS 2002 Structural basis for the inhibitory efficacy of efavirenz DMP-266 MSC194 and PNU142721 towards the HIV-1 RT K103N mutant Jimmy Lindberg1 Sn var Sigurdsson1 Seved Lowgren1 Hans O. Andersson1 Christer Sahlberg2 Rolf Noreen2 Kerstin Fridborg1 Hong Zhang2 and Torsten Unge1 1Department of Cell and Molecular Biology Uppsala Biomedical Center Uppsala University Sweden 2Medivir AB Huddinge Sweden The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combinationtherapy. The drugs Efavirenz MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and pNu142721 and MsC194 in complex with the K103N mutant. The structures unanimously indicate that the K103N substitution induces only minor positional adjustments of the three inhibitors and the residues lining the binding pocket. Thus compared to the corresponding wild-type structures these inhibitors bind to the mutant in a conservative mode rather than through major rearrangements. The structures implicate that the reduced inhibitory efficacy should be attributed to the changes in the chemical environment in the vicinity of the substituted N103 residue. This is supported by changes in hydrophobic and electrostatic interactions to the inhibitors between wild-type and K103N mutant complexes. These potent inhibitors accommodate to the K103N mutation by forming new interactions to the N103 side chain. Our results are consistent with the proposal by Hsiou et al. Hsiou Y. Ding J. Das K. Clark . Jr Boyer . Lewi P. Janssen . Kleim . Rosner M. Hughes . Arnold E. 2001 J. Mol. Biol. 309 437-445 that inhibitors with good activity against the K103N mutant would be expected