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Success in Determination of Whole Atom Positions in HIV-Protease
-Towards developing more effective anti-HIV drugs-
Mar. 10, 2009
HIV-1 protease is a dimeric aspartic protease that cleaves the nascent polyproteins of HIV-1 and plays an essential role in viral replication. Currently, the development of HIV-1 protease inhibitors is regarded as a major success of structure-based drug design, and the inhibitors of HIV-1 protease are important compounds to establish highly active anti-retroviral therapy for AIDS. To further understand the catalytic mechanism and inhibitor recognition of HIV-1 protease, we need to determine the locations of key hydrogen atoms in the catalytic aspartates Asp25 and Asp125. In this study, we employed neutron crystallography, since neutrons strongly interact with hydrogen and deuterium atoms, and neutron scattering lengths of hydrogen and deuterium atoms are very similar to those of carbon, nitrogen and oxygen atoms.
Results
(1) We have succeeded in preparing a large crystal of HIV-1 protease in complex with a transition-state analog inhibitor KNI-272.
(2) The structure of HIV-1 protease in complex with KNI-272 was determined by combined neutron crystallography at 1.9 Å resolution and X-ray crystallography at 1.4 Å resolution.
(3) The resulting structural data shows that the catalytic residue Asp25 is protonated and that Asp125 (the catalytic residue from the corresponding diad-related molecule) is deprotonated.
The results demonstrate that Asp25 provides a proton to the carbonyl group of the substrate and Asp125 contributes to activate the attacking water molecule as a nucleophile in the catalytic reaction. These provide direct experimental evidence for proposed aspects of the catalytic mechanism of HIV-1 protease; and can therefore contribute substantially to the development of specific inhibitors for therapeutic application.
•Success in Determination of Whole Atom Positions in HIV-Protease
-Towards developing more effective anti-HIV drugs-
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