HIV‐1 Protease: Structure, Dynamics, and Inhibition

Louis, John M.; Ishima, Rieko; Torchia, Dennis A.; Weber, Irene T.

doi:10.1016/s1054-3589(07)55008-8

Cited by 98 publications

(188 citation statements)

References 108 publications

Supporting

Mentioning

178

Contrasting

Order By: Relevance

“…As expected, DRV effectively blocked the dimerization (Fig. 2B), indicating that PDIs can block the dimerization of the PR monomers in the form of polyprotein as well as after autolysis (30,31). The dimerization of two identical PR monomers is required for the acquisition of PR catalytic activity (28,40), and the failure of PR dimerization should result in the loss of viral replication or compromised viral replication.…”

Section: Discussionsupporting

confidence: 70%

Loss of Protease Dimerization Inhibition Activity of Darunavir Is Associated with the Acquisition of Resistance to Darunavir by HIV-1

Koh

Aoki

Danish

et al. 2011

J Virol

View full text Add to dashboard Cite

Dimerization of HIV protease is essential for the acquisition of protease's proteolytic activity. We previously identified a group of HIV protease dimerization inhibitors, including darunavir (DRV). In the present work, we examine whether loss of DRV's protease dimerization inhibition activity is associated with HIV development of DRV resistance. Single amino acid substitutions, including I3A, L5A, R8A/Q, L24A, T26A, D29N, R87K, T96A, L97A, and F99A, disrupted protease dimerization, as examined using an intermolecular fluorescence resonance energy transfer (

show abstract

Section: Discussionsupporting

confidence: 70%

Loss of Protease Dimerization Inhibition Activity of Darunavir Is Associated with the Acquisition of Resistance to Darunavir by HIV-1

Koh

Aoki

Danish

et al. 2011

J Virol

View full text Add to dashboard Cite

show abstract

“…2B. This variant has displayed resistance to all nine FDA-approved inhibitors (2,43) and has been reported to cause up to a 32-fold reduction in inhibitor binding affinity (44). Our observation that the I84V transition structure is identical to that for the native enzyme indicates that the drug-resistant behavior that arises is independent from transition-state interactions.…”

Section: Resultsmentioning

confidence: 99%

Transition states of native and drug-resistant HIV-1 protease are the same

Kipp¹,

Hirschi²,

Wakata³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

HIV-1 protease is an important target for the treatment of HIV/ AIDS. However, drug resistance is a persistent problem and new inhibitors are needed. An approach toward understanding enzyme chemistry, the basis of drug resistance, and the design of powerful inhibitors is to establish the structure of enzymatic transition states. Enzymatic transition structures can be established by matching experimental kinetic isotope effects (KIEs) with theoretical predictions. However, the HIV-1 protease transition state has not been previously resolved using these methods. We have measured primary 14 at the carbonyl carbon, proton transfer to the amide nitrogen leaving group, and C-N bond cleavage. A transition structure consistent with the KIE values involves proton transfer from the active site Asp-125 (1.32 Å) with partial hydrogen bond formation to the accepting nitrogen (1.20 Å) and partial bond loss from the carbonyl carbon to the amide leaving group (1.52 Å). The KIEs measured for the native and I84V enzyme indicate nearly identical transition states, implying that a true transition-state analogue should be effective against both enzymes.aspartyl protease | protease mechanism | transition-state structure | drug design

show abstract

“…In addition, thermal fluctuations in DHFR promote the structural changes necessary for transition state assembly and, thereby, mediate the catalytic hydride transfer step (62). Functionally important excited states have also been identified in various enzymes, such as adenylate kinase (63), cyclophilin A (64), RNaseA (65), HIV-1 protease (66), and triosephosphate isomerase (65), with transition rates matching catalytic turnover numbers, providing evidence that conformational exchange plays an important role in regulating the rate of product formation for many of these enzymes. Some enzymes, such as cyclophilin A, exhibit fluctuations in the absence of substrate, indicating that their dynamics predispose them toward a functional form.…”

Section: Applications To Other Transient Conformersmentioning

confidence: 99%

NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers

Sekhar

Kay

2013

Proc. Natl. Acad. Sci. U.S.A.

233

202

View full text Add to dashboard Cite

The importance of dynamics to biomolecular function is becoming increasingly clear. A description of the structure-function relationship must, therefore, include the role of motion, requiring a shift in paradigm from focus on a single static 3D picture to one where a given biomolecule is considered in terms of an ensemble of interconverting conformers, each with potentially diverse activities. In this Perspective, we describe how recent developments in solution NMR spectroscopy facilitate atomic resolution studies of sparsely populated, transiently formed biomolecular conformations that exchange with the native state. Examples of how this methodology is applied to protein folding and misfolding, ligand binding, and molecular recognition are provided as a means of illustrating both the power of the new techniques and the significant roles that conformationally excited protein states play in biology.energy landscape | transiently and sparsely populated biomolecular states | invisible states | structure-function paradigmThe field of structural biology emerged from seminal X-ray diffraction studies of biomolecules such as DNA (1), myoglobin (2), hemoglobin (3), and lysozyme (4) that were carried out over 50 years ago. Since these landmark investigations, our knowledge of the relation between structure and function has greatly expanded, driven by significant improvements in both experimental and computational approaches and, of course, by the exponential increase in the number of structures that are now available. Despite tremendous advances, structural biology remains largely focused on studies of the lowest-energy conformational states of biomolecules, and although there are notable exceptions (5), the end game often remains the determination of a single static 3D structure that is then used as a starting point for understanding molecular function. It is becoming increasingly clear, however, that this narrow approach is not sufficient and that a description of molecular structure must take into account conformational fluctuations that can occur over a broad range of both time and length scales.The conformational space that can be explored by a given biomolecule is usually explained by invoking the concept of an energy landscape (6), a multidimensional hypersurface that governs the thermodynamics and kinetics of conformational transitions (7,8). Because biomolecular stability is dictated by the sum of a large number of attractive and repulsive interactions of similar strength, the resultant free-energy landscape is rugged (9), with the global minimum in the surface thought to correspond to the native state of the biomolecule. In addition, there are often local minima that are separated from the global minimum by free-energy barriers that can be overcome by thermal fluctuations. These low-lying conformationally excited states have remained elusive to quantitative investigation because their sparse population and transient nature complicates their study by conventional structural biology techniques that are so powerfu...

show abstract

HIV‐1 Protease: Structure, Dynamics, and Inhibition

Cited by 98 publications

References 108 publications

Loss of Protease Dimerization Inhibition Activity of Darunavir Is Associated with the Acquisition of Resistance to Darunavir by HIV-1

Loss of Protease Dimerization Inhibition Activity of Darunavir Is Associated with the Acquisition of Resistance to Darunavir by HIV-1

Transition states of native and drug-resistant HIV-1 protease are the same

NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers

Contact Info

Product

Resources

About