Nine Crystal Structures Determine the Substrate Envelope of the MDR HIV-1 Protease

Liu, Zhigang; Wang, Yong; Brunzelle, J.S.; Kovari, Iulia A.; Kovari, Ladislau C.

doi:10.1007/s10930-011-9316-2

Cited by 25 publications

(20 citation statements)

References 44 publications

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“…It should be noted that all of the crystal structures in group 5 were provided by two research groups. [29][30][31] The L63P mutation that is an amino substitution sometimes appeared in drug-resistant viruses 32,33) is seen in every cluster except for group 3.…”

Section: Resultsmentioning

confidence: 99%

A Cluster Analysis on the Structural Diversity of Protein Crystals, Exemplified by Human Immunodeficiency Virus Type 1 Protease

Fudo

Neya

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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Information on many protein crystal structures has recently become available due to developments in crystallographic techniques. Even for a single kind of protein, several and sometimes many crystal structures are available. Human immunodeficiency virus type 1 (HIV-1) protease is one of the most extensively studied viral proteins, and about six hundred crystal structures have been determined. In this work, we examined the structural diversity of HIV-1 protease, classifying crystal structures into several groups from the viewpoint of similarity in atom geometry. Using 499 crystal structures downloaded from the Protein Data Bank (PDB), cluster analysis was applied to the whole body of HIV-1 protease and also to a limited number of residues at the binding pocket. As a consequence of clustering with regard to the whole body, 499 crystal structures were separated into 6 groups. It was found that a major factor for this separation is the space group of the crystals and that the space group strongly depends on the agents used in the protein crystallization. Amino acid mutation is a minor factor for separation in clustering. In cluster analysis for a limited number of residues at the binding pocket, crystal structures were not distinctly separated, and no clear factor linked to the separation was clarified. The results suggest that amino acid mutations have little effect on the coordinates of the main-chain atoms of HIV-1 protease. Hence, the changes in drug efficacy or substrate fitness caused by mutations are mainly due to the physicochemical features of amino acid side chains.Key words clustering analysis; crystal structure; amino acid mutation; drug resistance; space group Due to the progress in techniques for protein crystallization and in software for model building, crystal structures of many proteins have been elucidated. The reliability of solved protein structures has also increased.1) The development of a high-energy X-ray source has also been important for advancing crystallographic studies.2) Due to the progress in crystallographic technology, the availability of crystal structures in good quality has enabled us to examine structural differences in proteins in detail. Even for a single kind of protein, an amino acid mutation will cause the difference in its activity. Mutagenesis is one of the best approaches for clarifying the relationship between the protein activity and the mutated amino acid residue. Since protein activity has a close relation with its structure, 3,4) it is of great interest in molecular biology that the influence of amino acid mutation induces the change in protein structure.Apart from artificial mutagenesis, amino acid mutation ceaselessly occurs in the process of evolution. There is a common consensus that the accumulation of amino acid mutations generates a genetic diversity and that the diversity is observed as a difference in protein function in phenotype. 5,6) In general, the mutation rate of viral proteins is much higher than that of protein in eukaryotes. Variants of a virus som...

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Section: Resultsmentioning

confidence: 99%

A Cluster Analysis on the Structural Diversity of Protein Crystals, Exemplified by Human Immunodeficiency Virus Type 1 Protease

Fudo

Neya

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…It is possible that these protease variants also alter substrate specificity (36,37). To see whether MDR HIV-1 protease variants can affect the order of the rates of the Gag and GagPro-Pol cleavage, we tested two MDR HIV-1 protease variants in our protease assay: PR G2 containing amino acid substitutions L10I, G48V, I54V, L63P, and V82A; and PR G4 containing amino acid substitutions L10I, L63P, A71V, G73S, I84V, and L90M.…”

Section: Inhibitor Resistance Mutations In Hiv-1 Protease Can Change mentioning

confidence: 99%

Context Surrounding Processing Sites Is Crucial in Determining Cleavage Rate of a Subset of Processing Sites in HIV-1 Gag and Gag-Pro-Pol Polyprotein Precursors by Viral Protease

Lee¹,

Potempa

Kolli

et al. 2012

Journal of Biological Chemistry

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“…The DetMDRs differ from isolates previously studied by our group in that these contain the major drug resistance mutations L33F, I47V, I50V, I54M, L76V, V82I/F, and I84F not present in the previous cohort 7, [16][17][18] ( Table 1). The DetMDRs also contain previously identified non-polymorphic accessory mutations L10V/G, V11I, I13V, K20T/R, L33F/I/M, K43T, F53L, A71L, T74P, and L89V.…”

Section: Introductionmentioning

confidence: 75%

The role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics

et al. 2014

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The role of mutantion in HIV-1 protease flap dynamics www.discoveriesjournals.org/discoveries 1 ♦ I47V HIV-1 mutation is involved in flap opening and the interaction between I47V and V32I tethers the flaps to the active site ♦ These findings are important in drug design strategies EXPERIMENTAL ArticleThe role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics ABSTRACT Treatment of Human Immunodeficiency Virus remains challenging due to the emergence of drug resistant strains under the selective pressure produced by standard anti-retroviral therapy. To explore the structural mechanisms of drug resistance, we performed 40 ns molecular dynamics simulations on three multi-drug resistant HIV-1 protease clinical isolates from patients attending an infectious diseases clinic in Detroit, MI. We identify a novel structural role for the I47V, V32I, I54M and L90M major resistance mutations in flap opening and closure of MDR-PR isolates. Our studies suggest I47V is involved in flap opening and the interaction between I47V and V32I tethers the flaps to the active site. Also, I54M and L90M may be responsible for asymmetric movement of the protease flaps. These findings can be utilized to improve drug design strategies against MDR HIV-1 PR variants.

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Nine Crystal Structures Determine the Substrate Envelope of the MDR HIV-1 Protease

Cited by 25 publications

References 44 publications

A Cluster Analysis on the Structural Diversity of Protein Crystals, Exemplified by Human Immunodeficiency Virus Type 1 Protease

A Cluster Analysis on the Structural Diversity of Protein Crystals, Exemplified by Human Immunodeficiency Virus Type 1 Protease

Context Surrounding Processing Sites Is Crucial in Determining Cleavage Rate of a Subset of Processing Sites in HIV-1 Gag and Gag-Pro-Pol Polyprotein Precursors by Viral Protease

The role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics

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