1a30
From Proteopedia
(New page: 200px<br /> <applet load="1a30" size="450" color="white" frame="true" align="right" spinBox="true" caption="1a30, resolution 2.0Å" /> '''HIV-1 PROTEASE COMPL...) |
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| - | [[Image:1a30.gif|left|200px]]<br /> | + | [[Image:1a30.gif|left|200px]]<br /><applet load="1a30" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1a30, resolution 2.0Å" /> | caption="1a30, resolution 2.0Å" /> | ||
'''HIV-1 PROTEASE COMPLEXED WITH A TRIPEPTIDE INHIBITOR'''<br /> | '''HIV-1 PROTEASE COMPLEXED WITH A TRIPEPTIDE INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The HIV-1 transframe region (TFR) is between the structural and functional | + | 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== | ==About this Structure== | ||
| - | 1A30 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http:// | + | 1A30 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A30 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Davies, D | + | [[Category: Davies, D R.]] |
[[Category: Dyda, F.]] | [[Category: Dyda, F.]] | ||
| - | [[Category: Kimmel, A | + | [[Category: Kimmel, A R.]] |
| - | [[Category: Louis, J | + | [[Category: Louis, J M.]] |
| - | [[Category: Nashed, N | + | [[Category: Nashed, N T.]] |
[[Category: aspartic protease]] | [[Category: aspartic protease]] | ||
[[Category: complex (aspartic protease/inhibitor)]] | [[Category: complex (aspartic protease/inhibitor)]] | ||
[[Category: hiv protease]] | [[Category: hiv protease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:40:15 2008'' |
Revision as of 09:40, 21 February 2008
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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. Active as HIV-1 retropepsin, with EC number 3.4.23.16 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
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