Expression, Characterisation and Mutagenesis of the Aspartic Proteinase from Equine Infectious Anaemia Virus

Powell, David J.; Bur, Daniel; Wlodawer, Alexander; Gustchina, Alla; Payne, Susan; Dunn, Ben M.; Kay, John

doi:10.1111/j.1432-1033.1996.00664.x

Cited by 17 publications

(20 citation statements)

References 29 publications

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“…This compound is a subnanomolar tide bonds on the right side of the inhibitor. Thus, the crystal inhibitor of HIV-1 PR, equally effective against wild-type EIAV form reported here represents a Case Of a potentially perfectly PR, with a measured K~ value of 0.1 nM (Powell et al, 1996).…”

Section: Inhibitor Binding Modementioning

confidence: 78%

“…The I54G mutant EIAV PR, however, had impaired activity toward some, but not all, of the 19 peptide substrates examined (Powell et al, 1996). These substrates had also been used previously in the characterization of native, mutant, and chimeric HIV-1 and HIV-2 PRs (Griffiths et al, 1992(Griffiths et al, , 1994.…”

Section: Comparison Of the Substrate-binding Sites Of Retroviral Protmentioning

confidence: 84%

“…In the I54G mutant of EIAV PR, the S3/S3' binding pockets are formed by the residues identical to those in the HIV-1 enzyme. Detailed results of the studies of substrate specificity of wild-type EIAV PR and several mutants, and limited structural interpretation of the kinetic data, are described elsewhere Powell et al, 1996).…”

Section: Comparison Of the Substrate-binding Sites Of Retroviral Protmentioning

confidence: 99%

“…EIAV PR can process HIV-derived substrates with efficiency comparable to that of HIV-1 and HIV-2 PRs (Tozser et al, 1992;Montelaro, 1994). However, EIAV PR is not susceptible to inhibition by a wide variety of the inhibitors that have been developed as anti-AIDS drugs (Wlodawer & Erickson, 1993;Powell et al, 1996), including those found to be promising clinical candidates. Mutations arising within the PR region of the HIV-1 genome as a consequence of selective drug pressure have been receiving increasing attention (Craig et al, 1993;Otto et al, 1993;Condra et al, 1995;Gulnik et al, 1995;Markowitz et al, 1995).…”

mentioning

confidence: 99%

“…We solved the structure of a mutant of EIAV PR in which Ile 54 (Powell et al, 1996; see Kinemage 1). This mutant was studied had been substituted with glycine (I54G) by the method of due to its much better expression properties than the native molecular replacement, using as a probe a homology-modeled EIAV PR.…”

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confidence: 99%

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Structure of equine infectious anemia virus proteinase complexed with an inhibitor

et al. 1996

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Equine infectious anemia virus (EIAV), the causative agent of infectious anemia in horses, is a member of the lentiviral family. The virus-encoded proteinase (PR) processes viral polyproteins into functional molecules during replication and it also cleaves viral nucleocapsid protein during infection. The X-ray structure of a complex of the I54G mutant of EIAV PR with the inhibitor HBY-793 was solved at 1.8 A resolution and refined to a crystallographic R-factor of 0.136. The molecule is a dimer in which the monomers are related by a crystallographic twofold axis. Although both the enzyme and the inhibitor are symmetric, the interactions between the central part of the inhibitor and the active site aspartates are asymmetric, and the inhibitor and the two flaps are partially disordered. The overall fold of EIAV PR is very similar to that of other retroviral proteinases. However, a novel feature of the EIAV PR structure is the appearance of the second a-helix in the monomer in a position predicted by the structural template for the family of aspartic proteinases. The parts of the EIAV PR with the highest resemblance to human immunodeficiency virus type 1 PR include the substrate-binding sites; thus, the differences in the specificity of both enzymes have to be explained by enzyme-ligand interactions at the periphery of the active site as well.

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Section: Inhibitor Binding Modementioning

confidence: 78%

Section: Comparison Of the Substrate-binding Sites Of Retroviral Protmentioning

confidence: 84%

Section: Comparison Of the Substrate-binding Sites Of Retroviral Protmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structure of equine infectious anemia virus proteinase complexed with an inhibitor

et al. 1996

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Toward a universal inhibitor of retroviral proteases: Comparative analysis of the interactions of LP‐130 complexed with proteases from HIV‐1, FIV, and EIAV

et al. 1998

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One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130 was found to be a universal, nanomolar-range inhibitor against all tested retroviral PRs. We solved the crystal structures of LP-130 in complex with retroviral PR5 from HIV-I, feline immunodeficiency virus, and equine infectious anemia virus and compared the structures to determine the differences in the interactions between the inhibitor and the active-site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor molecules. The only exceptions are the different conformations of naphthylalanine side chains at the P3/P3' positions, which might be responsible for the variation in the K; values. These findings indicate that successful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformational differences, despite the variations in the type of residues forming the active-site region. Although strong, specific interactions between the ligand and the enzyme might improve the potency of the inhibitor, the absence of such interactions seems to favor the universality of the compound. Hence, the ability of potential anti-AIDS drugs to inhibit multiple retroviral PRs might indicate their likelihood of not eliciting drug resistance. These studies may also contribute to the development of a small-animal model for preclinical testing of antiviral compounds.

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The Aspartic Proteinase from Equine Infectious Anaemia Virus

Powell

Bur

Wlodawer

et al. 1998

Aspartic Proteinases

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Expression, Characterisation and Mutagenesis of the Aspartic Proteinase from Equine Infectious Anaemia Virus

Cited by 17 publications

References 29 publications

Structure of equine infectious anemia virus proteinase complexed with an inhibitor

Structure of equine infectious anemia virus proteinase complexed with an inhibitor

Toward a universal inhibitor of retroviral proteases: Comparative analysis of the interactions of LP‐130 complexed with proteases from HIV‐1, FIV, and EIAV

The Aspartic Proteinase from Equine Infectious Anaemia Virus

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