X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor

Journal Article · Thu Nov 01 00:00:00 EST 1990 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.87.22.8805· OSTI ID:5700843

Swain, A L; Miller, M M; Wlodawer, A ^[1]; Green, J; Rich, D H ^[2]; Schneider, J ^[3]; Kent, S B.H. ^[4]

---

1. National Cancer Inst., Frederick, MD (United States)
2. Univ. of Wisconsin, Madison (United States)
3. California Inst. of Tech., Pasadena (United States)
4. California Inst. of Tech., Pasadena (United States) Bond Univ., Queensland (Australia)

The structure of a crystal complex of the chemically synthesized protease of human immunodeficiency virus 1 with a heptapeptide-derived inhibitor bound in the active site has been determined. The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-{psi} (CH(OH)CH{sub 2}N)-Pro-Ile-Val-OMe; the K{sub i} is 0.24 nM. The hydroxyethylamine moiety, in place of the normal scissile bond of the substrate, is believed to mimic a tetrahedral reaction intermediate. The structure of the complex has been refined to an R factor of 0.146 at 2.4-{angstrom} resolution by using restrained least squares with rms deviations in bond lengths of 0.02 {angstrom} and bond angles of 4{degree}. The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is positioned between the active site aspartate carboxyl groups within hydrogen bonding distance. Comparison of this structure with a reduced peptide bond inhibitor-protease complex indicates that these contacts confer the exceptional binding strength of JG-365.

• OSTI ID: 5700843
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 87:22; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
AIDS VIRUS
BIOCHEMICAL REACTION KINETICS
ENZYME INHIBITORS
X-RAY DIFFRACTION
PEPTIDE HYDROLASES
AMINO ACID SEQUENCE
BOND ANGLE
COHERENT SCATTERING
DIFFRACTION
ENZYMES
HYDROLASES
KINETICS
MICROORGANISMS
MOLECULAR STRUCTURE
ORGANIC COMPOUNDS
PARASITES
PROTEINS
REACTION KINETICS
SCATTERING
VIRUSES
550601* - Medicine- Unsealed Radionuclides in Diagnostics