scholarly journals Elucidation of the structure of retroviral proteases: a reminiscence

FEBS Journal ◽  
2015 ◽  
Vol 282 (21) ◽  
pp. 4059-4066 ◽  
Author(s):  
Mariusz Jaskolski ◽  
Maria Miller ◽  
J. K. Mohana Rao ◽  
Alla Gustchina ◽  
Alexander Wlodawer
Keyword(s):  
Retroviral Proteases

Cleavage of Vimentin by Different Retroviral Proteases

2000 ◽  
Vol 377 (2) ◽  
pp. 241-245 ◽  
Author(s):  
Jan Snášel ◽  
Robert Shoeman ◽  
Magda Hořejší ◽  
Olga Hrušková-Heidingsfeldová ◽  
Juraj Sedláček ◽  
...  
Keyword(s):  
Retroviral Proteases

scholarly journals HIV Protease: Historical Perspective and Current Research

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 839
Author(s):  
Irene T. Weber ◽  
Yuan-Fang Wang ◽  
Robert W. Harrison
Keyword(s):  
Molecular Mechanisms ◽  
Subsequent Development ◽  
Historical Background ◽  
Hiv Protease ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Evolution Of Resistance ◽  
Retroviral Proteases ◽  
And Function ◽  
Retroviral Protease

The retroviral protease of human immunodeficiency virus (HIV) is an excellent target for antiviral inhibitors for treating HIV/AIDS. Despite the efficacy of therapy, current efforts to control the disease are undermined by the growing threat posed by drug resistance. This review covers the historical background of studies on the structure and function of HIV protease, the subsequent development of antiviral inhibitors, and recent studies on drug-resistant protease variants. We highlight the important contributions of Dr. Stephen Oroszlan to fundamental knowledge about the function of the HIV protease and other retroviral proteases. These studies, along with those of his colleagues, laid the foundations for the design of clinical inhibitors of HIV protease. The drug-resistant protease variants also provide an excellent model for investigating the molecular mechanisms and evolution of resistance.

scholarly journals The Eukaryotic Translation Initiation Factor 4GI Is Cleaved by Different Retroviral Proteases

2003 ◽  
Vol 77 (23) ◽  
pp. 12392-12400 ◽  
Author(s):  
Enrique Álvarez ◽  
Luis Menéndez-Arias ◽  
Luis Carrasco
Keyword(s):  
Protein Synthesis ◽  
Virus Type ◽  
Leukemia Virus ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Intact Cells ◽  
Immunodeficiency Virus ◽  
Retroviral Proteases ◽  
Hiv 1

ABSTRACT The initiation factor eIF4G plays a central role in the regulation of translation. In picornaviruses, as well as in human immunodeficiency virus type 1 (HIV-1), cleavage of eIF4G by the viral protease leads to inhibition of protein synthesis directed by capped cellular mRNAs. In the present work, cleavage of both eIF4GI and eIF4GII has been analyzed by employing the proteases encoded within the genomes of several members of the family Retroviridae, e.g., Moloney murine leukemia virus (MoMLV), mouse mammary tumor virus, human T-cell leukemia virus type 1, HIV-2, and simian immunodeficiency virus. All of the retroviral proteases examined were able to cleave the initiation factor eIF4GI both in intact cells and in cell-free systems, albeit with different efficiencies. The eIF4GI hydrolysis patterns obtained with HIV-1 and HIV-2 proteases were very similar to each other but rather different from those obtained with MoMLV protease. Both eIF4GI and eIF4GII were cleaved very efficiently by the MoMLV protease. However, eIF4GII was a poor substrate for HIV proteases. Proteolytic cleavage of eIF4G led to a profound inhibition of cap-dependent translation, while protein synthesis driven by mRNAs containing internal ribosome entry site elements remained unaffected or was even stimulated in transfected cells.

scholarly journals The Dimer Interfaces of Protease and Extra-Protease Domains Influence the Activation of Protease and the Specificity of GagPol Cleavage

2003 ◽  
Vol 77 (1) ◽  
pp. 366-374 ◽  
Author(s):  
Steven C. Pettit ◽  
Sergei Gulnik ◽  
Lori Everitt ◽  
Andrew H. Kaplan
Keyword(s):  
Mutational Analysis ◽  
Expression System ◽  
Enzyme Activation ◽  
Nucleocapsid Proteins ◽  
Dimer Interface ◽  
Late Event ◽  
In The Wild ◽  
Retroviral Proteases ◽  
Hiv 1

ABSTRACT Activation of the human immunodeficiency virus type 1 (HIV-1) protease is an essential step in viral replication. As is the case for all retroviral proteases, enzyme activation requires the formation of protease homodimers. However, little is known about the mechanisms by which retroviral proteases become active within their precursors. Using an in vitro expression system, we have examined the determinants of activation efficiency and the order of cleavage site processing for the protease of HIV-1 within the full-length GagPol precursor. Following activation, initial cleavage occurs between the viral p2 and nucleocapsid proteins. This is followed by cleavage of a novel site located in the transframe domain. Mutational analysis of the dimer interface of the protease produced differential effects on activation and specificity. A subset of mutations produced enhanced cleavage at the amino terminus of the protease, suggesting that, in the wild-type precursor, cleavages that liberate the protease are a relatively late event. Replacement of the proline residue at position 1 of the protease dimer interface resulted in altered cleavage of distal sites and suggests that this residue functions as a cis-directed specificity determinant. In summary, our studies indicate that interactions within the protease dimer interface help determine the order of precursor cleavage and contribute to the formation of extended-protease intermediates. Assembly domains within GagPol outside the protease domain also influence enzyme activation.

scholarly journals Comparison of a retroviral protease in monomeric and dimeric states

2019 ◽  
Vol 75 (10) ◽  
pp. 904-917 ◽  
Author(s):  
Stanislaw Wosicki ◽  
Miroslaw Gilski ◽  
Helena Zabranska ◽  
Iva Pichova ◽  
Mariusz Jaskolski
Keyword(s):  
Water Molecule ◽  
Active Site ◽  
Biochemical Characterization ◽  
Extreme Case ◽  
Loop Region ◽  
Reducing Conditions ◽  
Crystallization Experiment ◽  
Dimeric Form ◽  
Retroviral Proteases ◽  
Interactive 3D

Retroviral proteases (RPs) are of high interest owing to their crucial role in the maturation process of retroviral particles. RPs are obligatory homodimers, with a pepsin-like active site built around two aspartates (in DTG triads) that activate a water molecule, as the nucleophile, under two flap loops. Mason–Pfizer monkey virus (M-PMV) is unique among retroviruses as its protease is also stable in the monomeric form, as confirmed by an existing crystal structure of a 13 kDa variant of the protein (M-PMV PR) and its previous biochemical characterization. In the present work, two mutants of M-PMV PR, D26N and C7A/D26N/C106A, were crystallized in complex with a peptidomimetic inhibitor and one mutant (D26N) was crystallized without the inhibitor. The crystal structures were solved at resolutions of 1.6, 1.9 and 2.0 Å, respectively. At variance with the previous study, all of the new structures have the canonical dimeric form of retroviral proteases. The protomers within a dimer differ mainly in the flap-loop region, with the most extreme case observed in the apo structure, in which one flap loop is well defined while the other flap loop is not defined by electron density. The presence of the inhibitor molecules in the complex structures was assessed using polder maps, but some details of their conformations remain ambiguous. In all of the presented structures the active site contains a water molecule buried deeply between the Asn26-Thr27-Gly28 triads of the protomers. Such a water molecule is completely unique not only in retropepsins but also in aspartic proteases in general. The C7A and C106A mutations do not influence the conformation of the protein. The Cys106 residue is properly placed at the homodimer interface area for a disulfide cross-link, but the reducing conditions of the crystallization experiment prevented S—S bond formation. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:Acta_Cryst_D:S2059798319011355.

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