Design, Activity, and 2.8 Å Crystal Structure of a
            <i>C</i>
            <sub>2</sub>
            Symmetric Inhibitor Complexed to HIV-1 Protease

Erickson, John W.; Neidhart, David J.; VanDrie, J.H.; Kempf, Dale J.; Wang, X.C; Norbeck, Daniel W.; Plattner, Jacob J.; Rittenhouse, Judith; Turon, Mary C.; Wideburg, Norman E.

doi:10.1126/science.2200122

Cited by 545 publications

(291 citation statements)

References 32 publications

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“…This approach was us. edto estimate the degree of adjustment required for accommodation of particular residues in the binding site of the enzyme, [14][15][16]18,19] show that the inhibitor is bound in an extended beta conformation, as was predicted by molecular modeling [20]. The conformation of the inhibitor is maintained by a series of hydrogen bond interactions between the C = 0 and NH groups of the inhibitor and atoms of the PR.…”

Section: Materials and Methodsmentioning

confidence: 99%

Studies on the role of the S₄ substrate binding site of HIV proteinases

et al. 1991

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Kinetic una )'sis of the hydrtd~sis of the I~ptide lI.Val,Ser.GIn,Asn.Tyr*Pro.ll¢.VaI.GIn.Nll~ and its analo$,t obtainctl by varyinll the !ength and introduein= substitutions at the P, site was carried out with t~flh HIV.I and ItlV.2 prolein~se~. Deletion or ih¢ t~rmlnal Vtd ~nd Gin had only metier|tie effect on ilia ~uhstrltte hydroly~h, while the d~lation of tli.c P.~. Set ~ts well as P; V,I Ilrcatly reduwd the substrata hydrolysis. Thi~ is pr~dicled to bc due to the loss of Intera,:tions betwoen main ~h~ins of the en,~yme ~ntl thtt substrata. $=bstitution of tile P,~ Ser h:,, amino =raids having high frequency 0f occurrenc~ in//turns resulted in llood substratcs, while larlle ~mino lteids were unfavorable in thi~ position. The two prntai=mses acted similarly, except for substrates havini! TItr, Val and Let= substitutions, which were I~=iler ,o;ommodated in the FIlV.2 substrata bindin$ pocket,

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Section: Materials and Methodsmentioning

confidence: 99%

Studies on the role of the S₄ substrate binding site of HIV proteinases

et al. 1991

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“…For example, the calculated a-carbon RMSD is 0.56 A. for HIV-1 protease inhibitors MVT-101 [29], JG-365 [35], U-85548e [36], A-74704 [37], and acetylpepstatin [38]. This strong overall backbone homology reduces the search space considerably and suggests that a very simple search algorithm should be effective.…”

Section: Docking the Mvt-io1 Inhibitor To Hiv-1 Proteasementioning

confidence: 99%

Empirical free energy as a target function in docking and design: application to HIV‐1 protease inhibitors

1996

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Structure-based drug design requires the development of efficient computer programs for exploring the structural compatibility of various flexible ligands with a given receptor. While various algorithms are available for finding docked conformations, selecting a target function that can reliably score the conformations remains a serious problem. We show that the use of an empirical free energy evaluation method, originally developed to characterize protein-protein interactions, can substantially improve the efficacy of search algorithms. In addition to the molecular mechanics interaction energy, the function takes account of solvation and side chain conformational entropy, while remaining simple enough to replace the incomplete target functions used in many drug docking and design procedures. The free energy function is used here in conjunction with a simple site mapping-fragment assembly algorithm, for docking the MVT-101 non-peptide inhibitor to HIV-1 protease. In particular, we predict the bound structure with an all atom RMSD of 1.21 A, compared to 1.69 A using an energy target function, and also accurately predict the free energy shifts obtained with a series of five trimeric hydroxyethylene isostere analogs.

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“…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.…”

mentioning

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. This suggests that the observed asymmetry of the protease in enzyme-inhibitor complexes may not be a consequence of the binding of an asymmetric inhibitor, but may be dictated by crystal packing interactions (Bone et al, 1991).…”

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confidence: 99%

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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Design, Activity, and 2.8 Å Crystal Structure of a C ₂ Symmetric Inhibitor Complexed to HIV-1 Protease

Cited by 545 publications

References 32 publications

Studies on the role of the S₄ substrate binding site of HIV proteinases

Studies on the role of the S₄ substrate binding site of HIV proteinases

Empirical free energy as a target function in docking and design: application to HIV‐1 protease inhibitors

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

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Design, Activity, and 2.8 Å Crystal Structure of a C 2 Symmetric Inhibitor Complexed to HIV-1 Protease

Cited by 545 publications

References 32 publications

Studies on the role of the S4 substrate binding site of HIV proteinases

Studies on the role of the S4 substrate binding site of HIV proteinases

Empirical free energy as a target function in docking and design: application to HIV‐1 protease inhibitors

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

Contact Info

Product

Resources

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Design, Activity, and 2.8 Å Crystal Structure of a C ₂ Symmetric Inhibitor Complexed to HIV-1 Protease

Studies on the role of the S₄ substrate binding site of HIV proteinases

Studies on the role of the S₄ substrate binding site of HIV proteinases