Interactions of substrates and inhibitors with a family of tethered HIV-1 and HIV-2 homo- and heterodimeric proteinases.

Griffiths, Jonathan T.; Tomchak, Lorraine; Mills, John; Graves, Mary C.; Cook, Neil D.; Dunn, Ben M.; Kay, John

doi:10.1016/s0021-9258(17)37613-5

Cited by 20 publications

(1 citation statement)

References 32 publications

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“…This "head-to-tail" arrangement is based on crystal structures of the native, twochain dimers which demonstrate that the N-and C-termini of different subunits are located within a few Å of each other. It has been shown that tethered dimers have a wildtype substrate specificity (Bhat et al, 1994;Cheng et al, 1990;Griffiths et al, 1994;Phylip et al, 1995). Crystallographic studies demonstrate that the structure of the single chain dimers is nearly identical to the native, two-chain protease (Bhat et al, 1994;Bhat et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Mutagenesis of the dimer interface residues of tethered and untethered HIV-1 protease result in differential activity and suggest multiple mechanisms of compensation

et al. 2003

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As is the case for all retroviruses, the protease of HIV-1 is only functional as a homodimer; dimerization of two protease monomers results in the formation of the enzyme active site. This dimer structure is supported primarily by interactions between the first four amino-terminal and the last four carboxy-terminal amino acids. These eight amino acids form a beta-sheet in which hydrophobic residues are oriented towards the core of the molecule and polar residues are directed towards the solvent. Although the structure of the dimer interface has been determined, the forces that support dimerization have not been fully characterized. Here, we describe a tethered construct in which two protease monomers are joined by a 5 amino acid linker. We evaluate the relative role of each dimer interface residue in functional homo- and heterodimers. Our studies indicate that the hydrophobic residues of the dimer interface are particularly important in maintaining enzyme activity and that enzyme activity is more sensitive to substitutions of the C-terminal amino acids. Further, we demonstrate that the presence of the tether is able to compensate for mutations within the dimer interface that inactivate the enzyme.

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Section: Introductionmentioning

confidence: 99%

Mutagenesis of the dimer interface residues of tethered and untethered HIV-1 protease result in differential activity and suggest multiple mechanisms of compensation

et al. 2003

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1.9 � x-ray study shows closed flap conformation in crystals of tethered HIV-1 PR

2001

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Convergent Chemical Synthesis and Crystal Structure of a 203 Amino Acid “Covalent Dimer” HIV‐1 Protease Enzyme Molecule

Torbeev

Kent

2007

Angewandte Chemie

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Enzymsynthese: Das große Potenzial kürzlich entwickelter Methoden zur vollständig konvergenten chemischen Synthese von Proteinen wird mit der Synthese der 203 Aminosäuren umfassenden „kovalent dimeren“ HIV‐1‐Protease belegt (siehe Bild). Das 21 870 Da schwere synthetische Protein hat die volle enzymatische Aktivität und die richtige dreidimensionale Struktur, wie eine hochauflösende Röntgenstrukturanalyse belegt.

show abstract

Interactions of substrates and inhibitors with a family of tethered HIV-1 and HIV-2 homo- and heterodimeric proteinases.

Cited by 20 publications

References 32 publications

Mutagenesis of the dimer interface residues of tethered and untethered HIV-1 protease result in differential activity and suggest multiple mechanisms of compensation

Mutagenesis of the dimer interface residues of tethered and untethered HIV-1 protease result in differential activity and suggest multiple mechanisms of compensation

1.9 � x-ray study shows closed flap conformation in crystals of tethered HIV-1 PR

Convergent Chemical Synthesis and Crystal Structure of a 203 Amino Acid “Covalent Dimer” HIV‐1 Protease Enzyme Molecule

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