1a30
From Proteopedia
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'''HIV-1 PROTEASE COMPLEXED WITH A TRIPEPTIDE INHIBITOR''' | '''HIV-1 PROTEASE COMPLEXED WITH A TRIPEPTIDE INHIBITOR''' | ||
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[[Category: Louis, J M.]] | [[Category: Louis, J M.]] | ||
[[Category: Nashed, N T.]] | [[Category: Nashed, N T.]] | ||
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Revision as of 06:44, 2 May 2008
HIV-1 PROTEASE COMPLEXED WITH A TRIPEPTIDE INHIBITOR
Overview
The HIV-1 transframe region (TFR) is between the structural and functional domains of the Gag-Pol polyprotein, flanked by the nucleocapsid and the protease domains at its N and C termini, respectively. Transframe octapeptide (TFP) Phe-Leu-Arg-Glu-Asp-Leu-Ala-Phe, the N terminus of TFR, and its analogues are competitive inhibitors of the action of the mature HIV-1 protease. The smallest, most potent analogues are tripeptides: Glu-Asp-Leu and Glu-Asp-Phe with Ki values of approximately 50 and approximately 20 microM, respectively. Substitution of the acidic amino acids in the TFP by neutral amino acids and d or retro-d configurations of Glu-Asp-Leu results in an >40-fold increase in Ki. Protease inhibition by Glu-Asp-Leu is dependent on a protonated form of a group with a pKa of 3.8; unlike other inhibitors of HIV-1 protease which are highly hydrophobic, Glu-Asp-Leu is extremely soluble in water, and its binding affinity decreases with increasing NaCl concentration. However, Glu-Asp-Leu is a poor inhibitor (Ki approximately 7.5 mM) of the mammalian aspartic acid protease pepsin. X-ray crystallographic studies at pH 4.2 show that the interactions of Glu at P2 and Leu at P1 of Glu-Asp-Leu with residues of the active site of HIV-1 protease are similar to those of other product-enzyme complexes. It was not feasible to understand the interaction of intact TFP with HIV-1 protease under conditions of crystal growth due to its hydrolysis giving rise to two products. The sequence-specific, selective inhibition of the HIV-1 protease by the viral TFP suggests a role for TFP in regulating protease function during HIV-1 replication.
About this Structure
1A30 is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease., Louis JM, Dyda F, Nashed NT, Kimmel AR, Davies DR, Biochemistry. 1998 Feb 24;37(8):2105-10. PMID:9485357 Page seeded by OCA on Fri May 2 09:44:04 2008
