Closing of the Flaps of HIV-1 Protease Induced by Substrate Binding:  A Model of a Flap Closing Mechanism in Retroviral Aspartic Proteases

Biochemistry ◽  
2006 ◽  
Vol 45 (21) ◽  
pp. 6606-6614 ◽  
Author(s):  
Gergely Tóth ◽  
Attila Borics
Keyword(s):  
Substrate Binding ◽  
Aspartic Proteases ◽  
Hiv 1 ◽  
Closing Mechanism

scholarly journals Host cell factors stimulate HIV-1 transcription by antagonizing substrate-binding function of Siah1 ubiquitin ligase to stabilize transcription elongation factor ELL2

2020 ◽  
Author(s):  
Jun Wu ◽  
Yuhua Xue ◽  
Xiang Gao ◽  
Qiang Zhou
Keyword(s):  
Host Cell ◽  
Stress Responses ◽  
Substrate Binding ◽  
Elongation Factor ◽  
Transcriptional Elongation ◽  
Elongation Complex ◽  
Binding Function ◽  
Cellular Stress Responses ◽  
Host Cell Factors ◽  
Hiv 1

Abstract The Siah1 and Siah2 ubiquitin ligases are implicated in diverse biological processes ranging from cellular stress responses, signaling to transcriptional regulation. A key substrate of Siah1 is ELL2, which undergoes proteolysis upon polyubiquitination. ELL2 stimulates transcriptional elongation and is a subunit of the Super Elongation Complex (SEC) essential for HIV-1 transactivation. Previously, multiple transcriptional and post-translational mechanisms are reported to control Siah's expression and activity. Here we show that the activity of Siah1/2 can also be suppressed by host cell factor 1 (HCF1), and the hitherto poorly characterized HCF2, which themselves are not degraded but can bind and block the substrate-binding domain (SBD) of Siah1/2 to prevent their autoubiquitination and trans-ubiquitination of downstream targets including ELL2. This effect stabilizes ELL2 and enhances the ELL2-SEC formation for robust HIV-1 transactivation. Thus, our study not only identifies HCF1/2 as novel activators of HIV-1 transcription through inhibiting Siah1 to stabilize ELL2, but also reveals the SBD of Siah1/2 as a previously unrecognized new target for HCF1/2 to exert this inhibition.

scholarly journals Aspartic Proteases ofPlasmodium falciparumas the Target of HIV‐1 Protease Inhibitors

2005 ◽  
Vol 191 (8) ◽  
pp. 1381-1382 ◽  
Author(s):  
Andrea Savarino ◽  
Roberto Cauda ◽  
Antonio Cassone
Keyword(s):  
Protease Inhibitors ◽  
Aspartic Proteases ◽  
Hiv 1

Electrostatics Plays a Crucial Role in HIV-1 Protease Substrate Binding, Drugs Fail to Take Advantage

Biochemistry ◽  
2020 ◽  
Vol 59 (36) ◽  
pp. 3316-3331
Author(s):  
Mohd Ahsan ◽  
Chinmai Pindi ◽  
Sanjib Senapati
Keyword(s):  
Crucial Role ◽  
Substrate Binding ◽  
Protease Substrate ◽  
Hiv 1

Substrate Binding Mechanism of HIV-1 Protease from Explicit-Solvent Atomistic Simulations

2009 ◽  
Vol 131 (33) ◽  
pp. 11811-11818 ◽  
Author(s):  
Fabio Pietrucci ◽  
Fabrizio Marinelli ◽  
Paolo Carloni ◽  
Alessandro Laio
Keyword(s):  
Substrate Binding ◽  
Atomistic Simulations ◽  
Binding Mechanism ◽  
Explicit Solvent ◽  
Hiv 1

Small hydroxyethylene-based peptidomimetics inhibiting both HIV-1 and C. albicans aspartic proteases

2003 ◽  
Vol 11 (22) ◽  
pp. 4719-4727 ◽  
Author(s):  
Alessandro Tossi ◽  
Fabio Benedetti ◽  
Stefano Norbedo ◽  
Damiano Skrbec ◽  
Federico Berti ◽  
...  
Keyword(s):  
Aspartic Proteases ◽  
Hiv 1

scholarly journals Ninety-Nine Is Not Enough: Molecular Characterization of Inhibitor-Resistant Human Immunodeficiency Virus Type 1 Protease Mutants with Insertions in the Flap Region

2008 ◽  
Vol 82 (12) ◽  
pp. 5869-5878 ◽  
Author(s):  
Milan Kožíšek ◽  
Klára Grantz Šašková ◽  
Pavlína Řezáčová ◽  
Jiří Brynda ◽  
Noortje M. van Maarseveen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Substrate Binding ◽  
Viral Resistance ◽  
Replication Capacity ◽  
Immunodeficiency Virus ◽  
Flap Region ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT While the selection of amino acid insertions in human immunodeficiency virus (HIV) reverse transcriptase (RT) is a known mechanism of resistance against RT inhibitors, very few reports on the selection of insertions in the protease (PR) coding region have been published. It is still unclear whether these insertions impact protease inhibitor (PI) resistance and/or viral replication capacity. We show that the prevalence of insertions, especially between amino acids 30 to 41 of HIV type 1 (HIV-1) PR, has increased in recent years. We identified amino acid insertions at positions 33 and 35 of the PR of HIV-1-infected patients who had undergone prolonged treatment with PIs, and we characterized the contribution of these insertions to viral resistance. We prepared the corresponding mutated, recombinant PR variants with or without insertions at positions 33 and 35 and characterized them in terms of enzyme kinetics and crystal structures. We also engineered the corresponding recombinant viruses and analyzed the PR susceptibility and replication capacity by recombinant virus assay. Both in vitro methods confirmed that the amino acid insertions at positions 33 and 35 contribute to the viral resistance to most of the tested PIs. The structural analysis revealed local structural rearrangements in the flap region and in the substrate binding pockets. The enlargement of the PR substrate binding site together with impaired flap dynamics could account for the weaker inhibitor binding by the insertion mutants. Amino acid insertions in the vicinity of the binding cleft therefore represent a novel mechanism of HIV resistance development.

scholarly journals HIV-1 Protease Substrate Binding and Product Release Pathways Explored with Coarse-Grained Molecular Dynamics

2007 ◽  
Vol 92 (12) ◽  
pp. 4179-4187 ◽  
Author(s):  
Joanna Trylska ◽  
Valentina Tozzini ◽  
Chia-en A. Chang ◽  
J. Andrew McCammon
Keyword(s):  
Molecular Dynamics ◽  
Substrate Binding ◽  
Coarse Grained ◽  
Product Release ◽  
Protease Substrate ◽  
Hiv 1 ◽  
Coarse Grained Molecular Dynamics
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