ArticleJournal of virology2006
Role of invariant Thr80 in human immunodeficiency virus type 1 protease structure, function, and viral infectivity.
Article in Journal of virology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- A synergy of activity, stability, and inhibitor-interaction of HIV-1 protease mutants evolved under drug-pressure.Protein science : a publication of the Protein Society · 2021Article
- NMR and MD studies combined to elucidate inhibitor and water interactions of HIV-1 protease and their modulations with resistance mutations.Journal of biomolecular NMR · 2019Article
- Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.ACS infectious diseases · 2019Article
- Predicting X-ray solution scattering from flexible macromolecules.Protein science : a publication of the Protein Society · 2018Article
- A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups.Viruses · 2017Article
- Modulation of HIV protease flexibility by the T80N mutation.Proteins · 2015Article
- An allosteric modulator of HIV-1 protease shows equipotent inhibition of wild-type and drug-resistant proteases.Journal of medicinal chemistry · 2014Article
- Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease.ACS chemical biology · 2013Article
- Differential Flap Dynamics in Wild-type and a Drug Resistant Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation.Journal of chemical theory and computation · 2012Article
- X-ray solution scattering studies of the structural diversity intrinsic to protein ensembles.Biopolymers · 2011Article
- Asymmetric total synthesis of (+)- and (-)-clusianone and (+)- and (-)-clusianone methyl enol ether via ACC alkylation and evaluation of their anti-HIV activity.Bioorganic & medicinal chemistry letters · 2011Article
- Carbamylation of N-terminal proline.ACS medicinal chemistry letters · 2010Article
- Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters.The FEBS journal · 2010Article
- Computational mutation scanning and drug resistance mechanisms of HIV-1 protease inhibitors.The journal of physical chemistry. B · 2010Article
- Co-lethality studied as an asset against viral drug escape: the HIV protease case.Biology direct · 2010Article
- Structure of the unbound form of HIV-1 subtype A protease: comparison with unbound forms of proteases from other HIV subtypes.Acta crystallographica. Section D, Biological crystallography · 2010Article
- In pursuit of virtual lead optimization: pruning ensembles of receptor structures for increased efficiency and accuracy during docking.Proteins · 2009Article
- Active-site mutations in the South african human immunodeficiency virus type 1 subtype C protease have a significant impact on clinical inhibitor binding: kinetic and thermodynamic study.Journal of virology · 2008Article
- Article
- Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir.Journal of molecular biology · 2008Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Sequence variability associated with human immunodeficiency virus type 1 (HIV-1) is useful for inferring structural and/or functional constraints at specific residues within the viral protease. Positions that are invariant even in the presence of drug selection define critically important residues for protease function. While the importance of conserved active-site residues is easily understood, the role of other invariant residues is not. This work focuses on invariant Thr80 at the apex of the P1 loop of HIV-1, HIV-2, and simian immunodeficiency virus protease. In a previous study, we postulated, on the basis of a molecular dynamics simulation of the unliganded protease, that Thr80 may play a role in the mobility of the flaps of protease. In the present study, both experimental and computational methods were used to study the role of Thr80 in HIV protease. Three protease variants (T80V, T80N, and T80S) were examined for changes in structure, dynamics, enzymatic activity, affinity for protease inhibitors, and viral infectivity. While all three variants were structurally similar to the wild type, only T80S was functionally similar. Both T80V and T80N had decreased the affinity for saquinavir. T80V significantly decreased the ability of the enzyme to cleave a peptide substrate but maintained infectivity, while T80N abolished both activity and viral infectivity. Additionally, T80N decreased the conformational flexibility of the flap region, as observed by simulations of molecular dynamics. Taken together, these data indicate that HIV-1 protease functions best when residue 80 is a small polar residue and that mutations to other amino acids significantly impair enzyme function, possibly by affecting the flexibility of the flap domain.
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