3TOF

HIV-1 Protease - Epoxydic Inhibitor Complex (pH 6 - Orthorombic Crystal form P212121)

Summary for 3TOF

• Entry DOI: 10.2210/pdb3tof/pdb
• Related PRD ID: PRD_001017
• Descriptor: Gag-Pol polyprotein, (S)-N-((1R,2S)-1-((2R,3R)-3-benzyloxiran-2-yl)-1-hydroxy-3-phenylpropan-2-yl)-3-methyl-2-(2-phenoxyacetamido)butanamide, ACETATE ION, ... (5 entities in total)
• Functional Keywords: hiv pr, epoxide, in-crystal reaction, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 (BRU ISOLATE) (HIV-1)
• Total number of polymer chains: 2
• Total formula weight: 22272.34

Authors

Geremia, S.,Olajuyigbe, F.M.,Ajele, J.O.,Demitri, N.,Randaccio, L.,Wuerges, J.,Benedetti, L.,Campaner, P.,Berti, F. (deposition date: 2011-09-05, release date: 2012-08-15, Last modification date: 2023-09-13)

Primary citation

Olajuyigbe, F.M.,Demitri, N.,De Zorzi, R.,Geremia, S.
Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals.
Molecules, 21:-, 2016

PubMed Abstract: Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions. The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.

PubMed: 27809253
DOI: 10.3390/molecules21111458

Experimental method

X-RAY DIFFRACTION (1.45 Å)