Structure at 2.5-.ANG. resolution of chemically synthesized Human Immunodeficiency Virus Type 1 protease complexed with a hydroxyethylene-based inhibitor

Jaskólski, Mariusz; Tomasselli, Alfredo G.; Sawyer, Tomi K.; Staples, Douglas G.; Heinrikson, Robert L.; Schneider, Jens; Kent, Stephen B. H.; Wlodawer, Alexander

doi:10.1021/bi00220a023

Cited by 236 publications

(198 citation statements)

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“…This has been reconciled with both the surface location of this turn ( Fig. 6; Kinemage 1) and its high thermal motion (Jaskolski et al, 1991), attributes common to &turns found in globular proteins (Rose et al, 1985). In a molecular dynamics simulation of HIV-1 protease, Harte et al (1990) found that the j3-sheet comprising residues 9-24 in each subunit formed the "fulcrum" of a molecular "cantilever," whereby movements in the enzyme flaps (residues 43-58) correlated with movements in the &sheet between residues 59 and 75.…”

Section: Discussionmentioning

confidence: 65%

“…The synthetic enzyme has been prepared in crystalline form and was used to solve the three-dimensional structure of both the native molecule and the enzyme complexed with several dif- ferent substrate-derived inhibitors Swain et al, 1990;Jaskolski et al, 1991). The chemical synthesis approach brings the entire world of organic chemistry into the realm of proteins.…”

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confidence: 99%

“…The range of chemical alterations that can be made to a native protein is limited only by the imagination and by any peculiarities of the particular chemical methodology being employed. In addition to the synthetic accessibility of the HIV-1 protease, knowledge of its three-dimensional structure Wlodawer et al, 1989;Erickson et al, 1990;Swain et al, 1990;Bone et al, 1991;Jaskolski et al, 1991) is invaluable in designing experiments to probe the interrelationship of enzyme structure with catalytic function.…”

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confidence: 99%

“…One intriguing aspect of the molecular function of HIV-1 protease is loss of C2 symmetry upon inhibitor (and presumably substrate) binding Erickson et al, 1990;Swain et al, 1990;Bone et al, 1991;Jaskolski et al, 1991). Even binding of C2 pseudosymmetric inhibitors (Erickson et al, 1990;Bone et al, 1991) apparently induces asymmetry in the enzyme.…”

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confidence: 99%

“…However, in the numerous protease-inhibitor complexes that have been solved, the geometry of this turn varies and is not necessarily identical in both subunits. For example, in the complex with JG-365, the geometries are type I' and 11' (Swain et al, 1990); with U85548e, type I' and I1 (Jaskolski et al, 1991); and with MVT-101, type I' and IV (Milier et al, 1989). In all cases, the residues of these turns possess high thermal factors, indicating high mobility (Jaskolski et al, 1991).…”

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confidence: 99%

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Structural engineering of the HIV‐1 protease molecule with a β‐turn mimic of fixed geometry

1993

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An important goal in the de novo design of enzymes is the control of molecular geometry. To this end, an analog of the protease from human immunodeficiency virus 1 (HIV-1 protease) was prepared by total chemical synthesis, containing a constrained, nonpeptidic type 11' 0-turn mimic of predetermined three-dimensional structure.The mimic &turn replaced residues GlyI6,l7 in each subunit of the homodimeric molecule. These residues constitute the central amino acids of two symmetry-related type I' 0-turns in the native, unliganded enzyme. The 0-turn mimic-containing enzyme analog was fully active, possessed the same substrate specificity as the GlyI67l7-containing enzyme, and showed enhanced resistance to thermal inactivation. These results indicate that the precise geometry of the @turn at residues 15-18 in each subunit is not critical for activity, and that replacement of the native sequence with a rigid 0-turn mimic can lead to enhanced protein stability. Finally, the successful incorporation of a fixed element of secondary structure illustrates the potential of a "molecular kit set" approach to protein design and synthesis.

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confidence: 65%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Structural engineering of the HIV‐1 protease molecule with a β‐turn mimic of fixed geometry

1993

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Analysis of the structure of chemically synthesized HIV-1 protease complexed with a hexapeptide inhibitor. Part I: Crystallographic refinement of 2 Å data

et al. 1997

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The structure of a complex between a hexapeptide-based inhibitor, MVT-101, and the chemically synthesized (Aba 67,95,167,195; Aba: L-a-amino-n-butyric acid) protease from the human immunodeficiency virus (HIV-1), reported previously at 2.3 Å has now been refined to a crystallographic R factor of 15.4% at 2.0 Å resolution. Root mean square deviations from ideality are 0.18 Å for bond lengths and 2.4° for the angles. The inhibitor can be fitted to the difference electron density map in two alternative orientations. Drastic differences are observed for positions and interactions at P3/S3 and P38/S38 subsites of the two orientations due to different crystallographic environments. Proteins 27:184-194 r 1997 Wiley-Liss, Inc. †

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Structural studies of FIV and HIV-1 proteases complexed with an efficient inhibitor of FIV protease

Li¹,

Morris²,

Lee³

et al. 2000

Proteins

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Three forms of feline immunodeficiency virus protease (FIV PR), the wild type (wt) and two single point mutants, V59I and Q99V, as well as human immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized with the C2-symmetric inhibitor, TL-3. The mutants of FIV PR were designed to replace residues involved in enzyme-ligand interactions by the corresponding HIV-1 PR residues at the structurally equivalent position. TL-3 shows decreased (improved) inhibition constants with these FIV PR mutants relative to wt FIV PR. Despite similar modes of binding of the inhibitor to all PRs (from P3 to P3'), small differences are evident in the conformation of the Phe side chains of TL-3 at the P1 and P1' positions in the complexes with the mutated FIV PRs. The differences mimick the observed binding of TL-3 in HIV-1 PR and correlate with a significant improvement in the inhibition constants of TL-3 with the two mutant FIV PRs. Large differences between the HIV-1 and FIV PR complexes are evident in the binding modes of the carboxybenzyl groups of TL-3 at P4 and P4'. In HIV-1 PR:TL-3, these groups bind over the flap region, whereas in the FIV PR complexes, the rings are located along the major axis of the active site. A significant difference in the location of the flaps in this region of the HIV-1 and FIV PRs correlates with the observed conformational changes in the binding mode of the peptidomimetic inhibitor at the P4 and P4' positions. These findings provide a structural explanation of the observed Ki values for TL-3 with the different PRs and will further assist in the development of improved inhibitors.

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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

Cited by 236 publications

References 39 publications

Structural engineering of the HIV‐1 protease molecule with a β‐turn mimic of fixed geometry

Structural engineering of the HIV‐1 protease molecule with a β‐turn mimic of fixed geometry

Analysis of the structure of chemically synthesized HIV-1 protease complexed with a hexapeptide inhibitor. Part I: Crystallographic refinement of 2 Å data

Structural studies of FIV and HIV-1 proteases complexed with an efficient inhibitor of FIV protease

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