The 3-D structure of HIV-1 proteinase and the design of antiviral agents for the treatment of AIDS

Blundell, Tom L.; Lapatto, Risto; Wilderspin, Andrew F.; Hemmings, Andrew M.; Hobart, Peter; Danley, Dennis E.; Whittle, Peter J.

doi:10.1016/0968-0004(90)90280-o

Cited by 84 publications

(58 citation statements)

References 33 publications

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“…Pioneering efforts have centered on inhibiting the viral protease that posttranslationally cleaves viral polyproteins (2,9,10,15). Since these early investigations, several laboratories have studied the X-ray crystallographic structures of the proteases complexed with protease inhibitors.…”

mentioning

confidence: 99%

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Logsdon¹,

Vickrey²,

Martin³

et al. 2004

J Virol

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mentioning

confidence: 99%

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Logsdon¹,

Vickrey²,

Martin³

et al. 2004

J Virol

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“…The three-dimensional (3-D) model was constructed from the alignment of the amino acid sequence of the PBP5fm C-terminal domain on the known 3-D structure of the ␤-lactamase of Staphylococcus aureus PC1 (25,26) by homology modeling with the COMPOSER programs (4,5,46,47). The model structure was then refined by energy minimization with AMBER (48).…”

mentioning

confidence: 99%

Structure of the low-affinity penicillin-binding protein 5 PBP5fm in wild-type and highly penicillin-resistant strains of Enterococcus faecium

et al. 1996

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Among its penicillin-binding proteins (PBPs), Enterococcus faecium possesses a low-affinity PBP5, PBP5fm, which is the main target involved in ␤-lactam resistance. A 7.7-kb EcoRI chromosomal fragment of E. faecium D63r containing the pbp5fm gene was cloned and sequenced. Two open reading frames (ORFs) were found. A 2,037-bp ORF encoded the deduced 73.8-kDa PBP5fm, the amino acid sequences of which were, respectively, 99.8, 78.5, and 62% homologous to those of the low-affinity plasmid-encoded PBP3r of Enterococcus hirae S185r and the chromosome-encoded PBP5 of E. hirae R40 and Enterococcus faecalis 56R. A second 597-bp ORF, designated psrfm, was found 2.3 kb upstream of pbp5fm. It appeared to be 285 bp shorter than and 74% homologous with the regulatory gene psr of E. hirae ATCC 9790. Different clinical isolates of E. faecium, for which a wide range of benzylpenicillin MICs were observed, showed that the increases in MICs were related to two mechanisms. For some strains of intermediate resistance (MICs of 16 to 64 g/ml), the increased level of resistance could be explained by the presence of larger quantities of PBP5fm which had an affinity for benzylpenicillin (second-order rate constant of protein acylation [k ؉2 /K] values of 17 to 25 M ؊1 s ؊1) that remained unchanged. For the two most highly resistant strains, EFM-1 (MIC, 90 g/ml) and H80721 (MIC, 512 g/ml), the resistance was related to different amino acid substitutions yielding very-low-affinity PBP5fm) which were synthesized in small quantities. More specifically, it appeared, with a three-dimensional model of the C-terminal domain of PBP5fm, that the substitutions of Met-485, located in the third position after the conserved SDN triad, by Thr in EFM-1 and by Ala in H80721 were the most likely cause of the decreasing affinity of PBP5fm observed in these strains.The genus Enterococcus, closely related to the genus Streptococcus, is involved in different clinical infections (37). Apart from their physiological properties, enterococci also differ from streptococci in that they generally are naturally 10-to 1,000-fold less susceptible to penicillins than streptococci (37). It was demonstrated that the natural low susceptibility of enterococci to penicillin is linked to the presence of at least one high-molecular-mass penicillin-binding protein (PBP) which has a low affinity for ␤-lactams (1, 17, 50). Enterococcus faecium appears to be the enterococcal species most resistant to ␤-lactam antibiotics, for which there are a wide range of benzylpenicillin MICs (0.5 to Ն 64 g/ml) for clinical isolates (22,30,50). Recently it became obvious that a new population of clinical E. faecium isolates for which the MICs of benzylpenicillin were very high (256 to 512 g/ml) had emerged in different countries (15,22,23,30).Among laboratory mutants and clinical isolates of E. faecium, two mechanisms have been shown to be involved in the high-level resistance to benzylpenicillin. These strains produced either an increased quantity of the essential low-affinity PBP5fm (15, 17) o...

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“…The buried threonine residue next to the catalytic aspartate residue in each Asp-Thr-Gly motif, which forms an important buried hydrogen-bond to a buried main-chain amide function, appears to be a critical structural restraint and an easily recognizable sequence motif. A similar symmetrical dimer was later predicted and identified in retroviral proteases from rous sarcoma and HIV [16], where the Asp-Thr-Gly sequence forms a similar role and retention of the dimeric form as a regulatory requirement in its activation appears to have provided an evolutionary selective advantage to the viruses.…”

Section: Protein Superfamiliesmentioning

confidence: 98%

Structural and functional restraints in the evolution of protein families and superfamilies

Gong

Worth

Bickerton

et al. 2009

Biochemical Society Transactions

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Divergent evolution of proteins reflects both selectively advantageous and neutral amino acid substitutions. In the present article, we examine restraints on sequence, which arise from selectively advantageous roles for structure and function and which lead to the conservation of local sequences and structures in families and superfamilies. We analyse structurally aligned members of protein families and superfamilies in order to investigate the importance of the local structural environment of amino acid residues in the acceptance of amino acid substitutions during protein evolution. We show that solvent accessibility is the most important determinant, followed by the existence of hydrogen bonds from the side-chain to main-chain functions and the nature of the element of secondary structure to which the amino acid contributes. Polar side chains whose hydrogen-bonding potential is satisfied tend to be more conserved than their unsatisfied or non-hydrogen-bonded counterparts, and buried and satisfied polar residues tend to be significantly more conserved than buried hydrophobic residues. Finally, we discuss the importance of functional restraints in the form of interactions of proteins with other macromolecules in assemblies or with substrates, ligands or allosteric regulators. We show that residues involved in such functional interactions are significantly more conserved and have differing amino acid substitution patterns.

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The 3-D structure of HIV-1 proteinase and the design of antiviral agents for the treatment of AIDS

Cited by 84 publications

References 33 publications

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Crystal Structures of a Multidrug-Resistant Human Immunodeficiency Virus Type 1 Protease Reveal an Expanded Active-Site Cavity

Structure of the low-affinity penicillin-binding protein 5 PBP5fm in wild-type and highly penicillin-resistant strains of Enterococcus faecium

Structural and functional restraints in the evolution of protein families and superfamilies

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