1EC1

HIV-1 protease in complex with the inhibitor BEA409

Summary for 1EC1

• Entry DOI: 10.2210/pdb1ec1/pdb
• Related: 1AJV 1AJX 1D4H 1D4I 1D4J 1EBW 1EBY 1EBZ 1EC0 1EC2 1EC3
• Descriptor: HIV-1 PROTEASE, N,N-[2,5-O-[DI-4-THIOPHEN-3-YL-BENZYL]-GLUCARYL]-DI-[VALYL-AMIDO-METHANE] (3 entities in total)
• Functional Keywords: dimer, protein-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366
• Total number of polymer chains: 2
• Total formula weight: 22386.49

Authors

Unge, T. (deposition date: 2000-01-25, release date: 2002-06-26, Last modification date: 2024-02-07)

Primary citation

Andersson, H.O.,Fridborg, K.,Lowgren, S.,Alterman, M.,Muhlman, A.,Bjorsne, M.,Garg, N.,Kvarnstrom, I.,Schaal, W.,Classon, B.,Karlen, A.,Danielsson, U.H.,Ahlsen, G.,Nillroth, U.,Vrang, L.,Oberg, B.,Samuelsson, B.,Hallberg, A.,Unge, T.
Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
Eur.J.Biochem., 270:1746-1758, 2003

PubMed Abstract: 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.

PubMed: 12694187
DOI: 10.1046/j.1432-1033.2003.03533.x

Experimental method

X-RAY DIFFRACTION (2.1 Å)