Structure of the unbound form of HIV-1 subtype A protease: comparison with unbound forms of proteases from other HIV subtypes

Robbins, A.H.; Coman, Roxana M.; Bracho-Sanchez, Edith; Fernandez, Marty A.; Gilliland, C. Taylor; Li, Mi; Agbandje‐McKenna, Mavis; Wlodawer, Alexander; Dunn, Ben M.; McKenna, Robert

doi:10.1107/s0907444909054298

Cited by 28 publications

(35 citation statements)

References 62 publications

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“…Human Immunodeficiency Virus-1 protease (HIV-1PR) is an essential enzyme in the replicative lifecycle of HIV (Louis, Ishima, Torchia, & Weber, 2007; Robbins et al, 2010). As such, it is a critical target in the management of infection (Agniswamy et al, 2012; Joint United Nations Programme on HIV/AIDS, 2010; Martinez-Cajas & Wainberg, 2007; Robbins et al, 2010; Wlodawer & Vondrasek, 1998).…”

Section: Perspective—conformational Sampling Of Hiv-1 Proteasementioning

confidence: 99%

“…As such, it is a critical target in the management of infection (Agniswamy et al, 2012; Joint United Nations Programme on HIV/AIDS, 2010; Martinez-Cajas & Wainberg, 2007; Robbins et al, 2010; Wlodawer & Vondrasek, 1998). HIV-1PR, shown in Fig.…”

Section: Perspective—conformational Sampling Of Hiv-1 Proteasementioning

confidence: 99%

“…Evidence for a large conformational opening of the flaps has been predicted from kinetic effects (Ermolieff, Lin, & Tang, 1997; Freedberg et al, 2002), nuclear magnetic resonance (NMR) studies (Huang et al, 2012, 2013; Ishima & Louis, 2008), and molecular dynamics (MD) simulations (Freedberg et al, 2002; Sadiq & De Fabritiis, 2010; Wittayanarakul et al, 2005). Several X-ray structures have been solved in a more “open-like” state (Agniswamy et al, 2012; Coman et al, 2008; Martin et al, 2005; Robbins et al, 2010; Weber, Agniswamy, Fu, Shen, & Harrison, 2012), but the flaps are not as wide open as seen in snap-shots from MD simulations (Fig. 2; Ding et al, 2008; Hornak et al, 2006b).…”

Section: Perspective—conformational Sampling Of Hiv-1 Proteasementioning

confidence: 99%

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Spin labeling and Double Electron-Electron Resonance (DEER) to Deconstruct Conformational Ensembles of HIV Protease

Casey

Fanucci

2015

Methods in Enzymology

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An understanding of macromolecular conformational equilibrium in biological systems is oftentimes essential to understand function, dysfunction, and disease. For the past few years, our lab has been utilizing site-directed spin labeling (SDSL), coupled with electron paramagnetic resonance (EPR) spectroscopy, to characterize the conformational ensemble and ligand-induced conformational shifts of HIV-1 protease (HIV-1PR). The biomedical importance of characterizing the fractional occupancy of states within the conformational ensemble critically impacts our hypothesis of a conformational selection mechanism of drug-resistance evolution in HIV-1PR. The purpose of the following chapter is to give a timeline perspective of our SDSL EPR approach to characterizing conformational sampling of HIV-1PR. We provide detailed instructions for the procedure utilized in analyzing distance profiles for HIV-1PR obtained from pulsed electron–electron double resonance (PELDOR). Specifically, we employ a version of PELDOR known as double electron–electron resonance (DEER). Data are processed with the software package “DeerAnalysis” (http://www.epr.ethz.ch/software), which implements Tikhonov regularization (TKR), to generate a distance profile from electron spin-echo amplitude modulations. We assign meaning to resultant distance profiles based upon a conformational sampling model, which is described herein. The TKR distance profiles are reconstructed with a linear combination of Gaussian functions, which is then statistically analyzed. In general, DEER has proven powerful for observing structural ensembles in proteins and, more recently, nucleic acids. Our goal is to present our advances in order to aid readers in similar applications.

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Section: Perspective—conformational Sampling Of Hiv-1 Proteasementioning

confidence: 99%

Section: Perspective—conformational Sampling Of Hiv-1 Proteasementioning

confidence: 99%

Section: Perspective—conformational Sampling Of Hiv-1 Proteasementioning

confidence: 99%

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Spin labeling and Double Electron-Electron Resonance (DEER) to Deconstruct Conformational Ensembles of HIV Protease

Casey

Fanucci

2015

Methods in Enzymology

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“…The .pdb file for the crystal structure of native HIV-1 PR protein subtype A (PDB ID: 3ixo) [10] was obtained from the protein data bank (PDB) [16]. The designed analogs S1 and S2 were obtained as 3D models and flexible docking with HIV-PR protein subtype-A (PDB ID: 3ixo) were performed.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of novel Saquinavir analogs for resistance mutation compatibility and potential as an HIV-Protease inhibitor drug

Jayaswal

Mishra

et al. 2014

Bioinformation

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A fundamental issue related to therapy of HIV-1 infection is the emergence of viral mutations which severely limits the long term efficiency of the HIV-protease (HIV-PR) inhibitors. Development of new drugs is therefore continuously needed. Chemoinformatics enables to design and discover novel molecules analogous to established drugs using computational tools and databases. Saquinavir, an anti-HIV Protease drug is administered for HIV therapy. In this work chemoinformatics tools were used to design structural analogs of Saquinavir as ligand and molecular dockings at AutoDock were performed to identify potential HIV-PR inhibitors. The analogs S1 and S2 when docked with HIV-PR had binding energies of -4.08 and -3.07 kcal/mol respectively which were similar to that for Saquinavir. The molecular docking studies revealed that the changes at N2 of Saquinavir to obtain newly designed analogs S1 (having N2 benzoyl group at N1) and S2 (having 3-oxo-3phenyl propanyl group at N2) were able to dock with HIV-PR with similar affinity as that of Saquinavir. Docking studies and computationally derived pharmacodynamic and pharmacokinetic properties׳ comparisons at ACD/I-lab establish that analog S2 has more potential to evade the problem of drug resistance mutation against HIV-1 PR subtype-A. S2 can be further developed and tested clinically as a real alternative drug for HIV-1 PR across the clades in future.

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“…The 3D structures of chain A's of 1T2D, 1T24, 1U4O, 1U5A, 1XIV, 2A94 and 4B7U ( Figure 1) were then analysed for structure assessment by ANOLEA [7][8][9][10][11][12][13].…”

Section: D Structural Analysis Of Pdb Entriesmentioning

confidence: 99%

In-Silico Assessment of Various PDB Entries of Pfldh Enzyme for their Use in SBDD

Shrivastava¹,

Kumar²

2016

Chem Inform

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Structure of the unbound form of HIV-1 subtype A protease: comparison with unbound forms of proteases from other HIV subtypes

Cited by 28 publications

References 62 publications

Spin labeling and Double Electron-Electron Resonance (DEER) to Deconstruct Conformational Ensembles of HIV Protease

Spin labeling and Double Electron-Electron Resonance (DEER) to Deconstruct Conformational Ensembles of HIV Protease

Evaluation of novel Saquinavir analogs for resistance mutation compatibility and potential as an HIV-Protease inhibitor drug

In-Silico Assessment of Various PDB Entries of Pfldh Enzyme for their Use in SBDD

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