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Epsins are endocytic proteins with a structured epsin N-terminal homology (ENTH) domain that binds phosphoinositides and a poorly structured C-terminal region that interacts with ubiquitin and endocytic machinery, including clathrin and endocytic scaffolding proteins. Yeast has two redundant genes encoding epsins, ENT1 and ENT2; deleting both genes is(More)
The binding and the energetics of the interaction of cholera toxin with the oligosaccharide portion of ganglioside GM1 (oligo-GM1), the toxin cell surface receptor, have been studied by high-sensitivity isothermal titration calorimetry and differential scanning calorimetry. Previously, we have shown that the association of cholera toxin to ganglioside GM1(More)
When interacting with the CD4 receptor, the HIV gp120 envelope glycoprotein undergoes conformational changes that allow binding to the chemokine receptor. Receptor binding is proposed to lead to conformational changes in the gp41 transmembrane envelope glycoprotein involving the creation and/or exposure of a coiled coil consisting of three heptad repeat(More)
The appearance of viral strains that are resistant to protease inhibitors is one of the most serious problems in the chemotherapy of HIV-1/AIDS. The most pervasive drug-resistant mutants are those that affect all inhibitors in clinical use. In this paper, we have characterized a multiple-drug-resistant mutant of the HIV-1 protease that affects indinavir,(More)
The non-specific binding of a drug to plasma proteins is an important determinant of its biological efficacy since it modulates the availability of the drug to its intended target. In the case of HIV-1 protease inhibitors, binding to human serum albumin (HSA) and alpha(1)-acid glycoprotein (AAG) appears to be an important modulator of drug bioavailability.(More)
Lis1, Nudel/NudE, and dynactin are regulators of cytoplasmic dynein, a minus end-directed, microtubule (MT)-based motor required for proper spindle assembly and orientation. In vitro studies have shown that dynactin promotes processive movement of dynein on MTs, whereas Lis1 causes dynein to enter a persistent force-generating state (referred to here as(More)
As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not(More)
The theory of the binding polynomial constitutes a very powerful formalism by which many experimental biological systems involving ligand binding can be analyzed under a unified framework. The analysis of isothermal titration calorimetry (ITC) data for systems possessing more than one binding site has been cumbersome because it required the user to develop(More)
The initial events of HIV-1 cell infection involve the sequential binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor and the coreceptor, usually CCR5 or CXCR4. Binding to the coreceptor triggers the chain of events that culminates with the entry of the virus into the cell. In this process, the interaction of gp120 with the(More)
The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a sub-micromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50(More)