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Structure at 2.5-.ANG. resolution of chemically synthesized Human Immunodeficiency Virus Type 1 protease complexed with a hydroxyethylene-based inhibitor
Abstract
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.
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Metadata
- Authors
- Jaskolski, M., Tomasselli, A. G., Sawyer, T. K., Staples, D. G., Heinrikson, R. L., Schneider, J., Kent, S. B. H., & Wlodawer, A.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1991-02-12
- Volume
- 30
- Issue
- 6
- Pages
- 1600-1609
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W1965349185
- Cited by
- 227
- References
- 36
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 4 · 2012: 6
- FWCI
- 26.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01co074101-034)
- National Cancer Institute (N01 CO-74101)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- HIV-1 protease, protease-inhibitor complex, substrate-based inhibitors, flap conformation, enzyme mechanism
- MeSH terms
- Amino Acid Sequence, Ethylenes, Indicators and Reagents, Models, Molecular, Molecular Sequence Data, Oligopeptides, Protease Inhibitors, Protein Conformation, Thermodynamics, X-Ray Diffraction, HIV-1, HIV Protease
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