1d4j
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HIV-1 protease in complex with the inhibitor MSL370
OverviewOverview
HIV-1 protease is an important target for treatment of AIDS, and efficient, drugs have been developed. However, the resistance and negative side, effects of the current drugs has necessitated the development of new, compounds with different binding patterns. In this study, nine, C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with, the enzyme, the crystal structures analysed at 1.8-2.3 A resolution, and, the inhibitory activity of the compounds characterized in order to, evaluate the effects of the individual modifications. These compounds, comprise two central hydroxy groups that mimic the geminal hydroxy groups, of a cleavage-reaction intermediate. One of the hydroxy groups is located, between the delta-oxygen atoms of the two catalytic aspartic acid, residues, and the other in the gauche position relative to the first. The, asymmetric binding of the two central inhibitory hydroxyls induced a small, deviation from exact C2 symmetry in the whole enzyme-inhibitor complex., The study shows that the protease molecule could accommodate its structure, to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the, S3/S3' sites was exploited by elongation of the compounds with groups in, the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the, protease and the inhibitors. This study produced a number of inhibitors, with Ki values in the 100 picomolar range.
About this StructureAbout this Structure
1D4J is a Single protein structure of sequence from Human immunodeficiency virus with MSC as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
ReferenceReference
Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors., Andersson HO, Fridborg K, Lowgren S, Alterman M, Muhlman A, Bjorsne M, Garg N, Kvarnstrom I, Schaal W, Classon B, Karlen A, Danielsson UH, Ahlsen G, Nillroth U, Vrang L, Oberg B, Samuelsson B, Hallberg A, Unge T, Eur J Biochem. 2003 Apr;270(8):1746-58. PMID:12694187
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