1tcx
From Proteopedia
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'''HIV TRIPLE MUTANT PROTEASE COMPLEXED WITH INHIBITOR SB203386''' | '''HIV TRIPLE MUTANT PROTEASE COMPLEXED WITH INHIBITOR SB203386''' | ||
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Revision as of 06:48, 3 May 2008
HIV TRIPLE MUTANT PROTEASE COMPLEXED WITH INHIBITOR SB203386
Overview
To gain greater understanding of the structural basis of human immunodeficiency virus (HIV) protease ligand specificity, we have crystallized and determined the structures of the HIV-1 protease (Val32Ile, Ile47Val, Val82Ile) triple mutant and simian immunodeficiency virus (SIV) protease in complex with SB203386, a tripeptide analogue inhibitor containing a C-terminal imidazole substituent as an amide bond isostere. SB203386 is a potent inhibitor of HIV-1 protease (Ki = 18 nM) but shows decreased inhibition of the HIV-1 protease (Val32Ile, Ile47Val, Val82Ile) triple mutant (Ki = 112 nM) and SIV protease (Ki = 960 nM). Although SB203386 binds in the active site cavity of the triple mutant in a similar fashion to its binding to the wild-type HIV-1 protease [Abdel-Meguid et al. (1994) Biochemistry 33, 11671], it binds to SIV protease in an unexpected mode showing two inhibitor molecules each binding to half of the active site. Comparison of these two structures and that of the wild-type HIV-1 protease bound to SB203386 reveals that HIV protease ligand specificity is imparted by residues outside of the catalytic pocket, which causes subtle changes in its shape. Furthermore, this work illustrates the importance of structural studies in order to understand the structure-activity relationship (SAR) between related enzymes.
About this Structure
1TCX is a Single protein structure of sequence from Human immunodeficiency virus. Full crystallographic information is available from OCA.
Reference
Human immunodeficiency virus protease ligand specificity conferred by residues outside of the active site cavity., Hoog SS, Towler EM, Zhao B, Doyle ML, Debouck C, Abdel-Meguid SS, Biochemistry. 1996 Aug 13;35(32):10279-86. PMID:8756683 Page seeded by OCA on Sat May 3 09:48:20 2008
