ABSTRACT
Faldaprevir analogue molecule (FAM) has been reported to effectively inhibit the catalytic activity of HCV NS3/4A protease, making it a potential lead compound against HCV. A series of HCV NS3/4A protease crystal structures were analyzed by bioinformatics methods, and the FAM-HCV NS3/4A protease crystal structure was chosen for this study. A 20.4 ns molecular dynamics simulation of the complex consists of HCV NS3/4A protease and FAM was conducted. The key amino acid residues for interaction and the binding driving force for the molecular recognition between the protease and FAM were identified from the hydrogen bonds and binding free energy analyses. With the driving force of hydrogen bonds and van der Waals, FAM specifically bind to the active pocket of HCV NS3/4A protease, including V130-S137, F152-D166, D77-D79 and V55, which agreed with the experimental data. The effect of R155K, D168E/V and V170T site-directed mutagenesis on FAM molecular recognition was analyzed for their effect on drug resistance, which provided the possible molecular explanation of FAM resistance. Finally, the system conformational change was explored by using free energy landscape and conformational cluster. The result showed four kinds of dominant conformation, which provides theoretical basis for subsequent design of Faldaprevir analogue inhibitors based on the structure of HCV NS3/4A protease.
Subject(s)
Antiviral Agents , Chemistry , Carrier Proteins , Chemistry , Drug Resistance, Viral , Endopeptidases , Hepacivirus , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Oligopeptides , Chemistry , Protease Inhibitors , Chemistry , Serine Proteases , Thiazoles , Chemistry , Viral Nonstructural Proteins , ChemistryABSTRACT
With the understanding of the development and pro-gress of the cancer,the research of targeted cancer drug devel-opment reaches into a new era.p53 is an important tumor sup-pressor gene,the protein coded by p53 plays a critical role in tumor suppression mainly by inducing cell cycle regulation, DNA repair and apoptosis.Nowadays,p53 becomes a relatively attractive target for anti-cancer drug development and there are some drugs targeting p53,moreover,APR-246 which targets mutant p53 is in Phase II clinical trial.In addition,it facilitates drugs discovery programmes in the challenging area of protein-protein interactions and mutant protein conformational change. The review discusses the research progress of drugs which target p53 and elucidates the characteristics and mechanisms of these compounds.
ABSTRACT
The Ca2+-ATPase of sarcoplasmic reticulum is a Ca2+ pump that plays a key role in regulating cytosol calcium concentration in muscle cells. It undergoes a sequential conformational transition during the transport process. According to the classical E1/E2 theory, in the E1 state the binding sites have high affinity and open to the cytoplasm, whereas in the E2 state the binding sites have low affinity and face the luminal side. Crystal structures of several states during the reaction cycle of Ca2+-ATPase have been solved recently, including a Ca2+-bound form (E1-2Ca2+), a Ca2+-unbound form stabilized by a potent inhibitor thapsigargin (TG) (E2-TG), an ATP-bound form (E1-ATP), an E1-P-ADP state, and an E2-Pi state. The details of these crystal structures and the relationship between structure and function of Ca2+-ATPase during reaction cycle were summarized, and the issues to be addressed in future research were raised.
ABSTRACT
The DegP protein, functioning as both chaperone and protease, plays a critical role in degrading and removing denatured or damaged proteins in the cellular envelope during heat shock and other stresses. So far, several proteins have been identified as its natural targets. A carboxyle-terminal peptide derived from the PapG pilus, one of the in vivo substrates for DegP, has been shown to activate the protease. Nevertheless, neither the details nor the physiological implications of such activation have been studied. The evidence that DegP undergoes conformational changes upon binding the peptide derived from C-terminal sequence of pilus subunit PapG has been presented. It demonstrated that upon binding this peptide, detectable changes can be observed for both secondary and tertiary structures of DegP, as examined by CD spectroscopy. Gel filtration and dynamic light scattering analysis also revealed that the size of DegP becomes smaller to a minor extent. Moreover, both the hydrophobic surfaces and catalytic sites of DegP were found to expose slightly in the presence of the peptide. Upon peptide binding, a less flexible and more rigid conformation of DegP was obtained as analyzed by fluorescence anisotropy. The physiological implications of these observations for DegP are discussed.