8hvp
From Proteopedia
(New page: 200px<br /> <applet load="8hvp" size="450" color="white" frame="true" align="right" spinBox="true" caption="8hvp, resolution 2.5Å" /> '''STRUCTURE AT 2.5-ANG...) |
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caption="8hvp, resolution 2.5Å" /> | caption="8hvp, resolution 2.5Å" /> | ||
'''STRUCTURE AT 2.5-ANGSTROMS RESOLUTION OF CHEMICALLY SYNTHESIZED HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE COMPLEXED WITH A HYDROXYETHYLENE*-BASED INHIBITOR'''<br /> | '''STRUCTURE AT 2.5-ANGSTROMS RESOLUTION OF CHEMICALLY SYNTHESIZED HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE COMPLEXED WITH A HYDROXYETHYLENE*-BASED INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The crystal structure of a complex between chemically synthesized human | + | The crystal structure of a complex between chemically synthesized human immunodeficiency virus type 1 (HIV-1) protease and an octapeptide inhibitor has been refined to an R factor of 0.138 at 2.5-A resolution. The substrate-based inhibitor, H-Val-Ser-Gln-Asn-Leu psi [CH(OH)CH2]Val-Ile-Val-OH (U-85548e) contains a hydroxyethylene isostere replacement at the scissile bond that is believed to mimic the tetrahedral transition state of the proteolytic reaction. This potent inhibitor has Ki less than 1 nM and was developed as an active-site titrant of the HIV-1 protease. The inhibitor binds in an extended conformation and is involved in beta-sheet interactions with the active-site floor and flaps of the enzyme, which form the substrate/inhibitor cavity. The inhibitor diastereomer has the S configuration at the chiral carbon atom of the hydroxyethylene insert, and the hydroxyl group is within H-bonding distance of the two active-site carboxyl groups in the enzyme dimer. The two subunits of the enzyme are related by a pseudodyad, which superposes them at a 178 degrees rotation. The main difference between the subunits is in the beta turns of the flaps, which have different conformations in the two monomers. The inhibitor has a clear preferred orientation in the active site and the alternative conformation, if any, is a minor one (occupancy of less than 30%). A new model of the enzymatic mechanism is proposed in which the proteolytic reaction is viewed as a one-step process during which the nucleophile (water molecule) and electrophile (an acidic proton) attack the scissile bond in a concerted manner. |
==About this Structure== | ==About this Structure== | ||
| - | 8HVP 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]. Full crystallographic information is available from [http:// | + | 8HVP 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]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HVP OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Heinrikson, R | + | [[Category: Heinrikson, R L.]] |
[[Category: Jaskolski, M.]] | [[Category: Jaskolski, M.]] | ||
| - | [[Category: Kent, S | + | [[Category: Kent, S B.H.]] |
[[Category: Miller, M.]] | [[Category: Miller, M.]] | ||
| - | [[Category: Sawyer, T | + | [[Category: Sawyer, T K.]] |
[[Category: Schneider, J.]] | [[Category: Schneider, J.]] | ||
| - | [[Category: Staples, D | + | [[Category: Staples, D G.]] |
| - | [[Category: Tomasselli, A | + | [[Category: Tomasselli, A G.]] |
[[Category: Wlodawer, A.]] | [[Category: Wlodawer, A.]] | ||
[[Category: hydrolase(acid proteinase)]] | [[Category: hydrolase(acid proteinase)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:17:53 2008'' |
Revision as of 17:17, 21 February 2008
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STRUCTURE AT 2.5-ANGSTROMS RESOLUTION OF CHEMICALLY SYNTHESIZED HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 PROTEASE COMPLEXED WITH A HYDROXYETHYLENE*-BASED INHIBITOR
Overview
The crystal structure of a complex between chemically synthesized human immunodeficiency virus type 1 (HIV-1) protease and an octapeptide inhibitor has been refined to an R factor of 0.138 at 2.5-A resolution. The substrate-based inhibitor, H-Val-Ser-Gln-Asn-Leu psi [CH(OH)CH2]Val-Ile-Val-OH (U-85548e) contains a hydroxyethylene isostere replacement at the scissile bond that is believed to mimic the tetrahedral transition state of the proteolytic reaction. This potent inhibitor has Ki less than 1 nM and was developed as an active-site titrant of the HIV-1 protease. The inhibitor binds in an extended conformation and is involved in beta-sheet interactions with the active-site floor and flaps of the enzyme, which form the substrate/inhibitor cavity. The inhibitor diastereomer has the S configuration at the chiral carbon atom of the hydroxyethylene insert, and the hydroxyl group is within H-bonding distance of the two active-site carboxyl groups in the enzyme dimer. The two subunits of the enzyme are related by a pseudodyad, which superposes them at a 178 degrees rotation. The main difference between the subunits is in the beta turns of the flaps, which have different conformations in the two monomers. The inhibitor has a clear preferred orientation in the active site and the alternative conformation, if any, is a minor one (occupancy of less than 30%). A new model of the enzymatic mechanism is proposed in which the proteolytic reaction is viewed as a one-step process during which the nucleophile (water molecule) and electrophile (an acidic proton) attack the scissile bond in a concerted manner.
About this Structure
8HVP is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor., Jaskolski M, Tomasselli AG, Sawyer TK, Staples DG, Heinrikson RL, Schneider J, Kent SB, Wlodawer A, Biochemistry. 1991 Feb 12;30(6):1600-9. PMID:1993177
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