SLITHER: a web server for generating contiguous conformations of substrate molecules entering into deep active sites of proteins or migrating through channels in membrane transporters

Lee, Po-Hsien; Kuo, Kuan‐Ting; Liu, Eric Minwei; Lin, Jung‐Hsin

doi:10.1093/nar/gkp359

Cited by 32 publications

(24 citation statements)

References 25 publications

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“…MEDock is an algorithm based on Maximum Entropy docking for study of protein-ligand docking and interaction [13, 14]. MEDock has been applied to small molecule-protein docking, as well as large biomolecule-protein docking (DNA-protein docking).…”

Section: Resultsmentioning

confidence: 99%

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In vitro selection of RNA aptamers that inhibit the activity of type A botulinum neurotoxin

Chang

Blank

Janardhanan

et al. 2010

Biochemical and Biophysical Research Communications

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The category A agent, botulinum neurotoxin (BoNT), is the most toxic molecule known to mankind. The endopeptidase activity of light chain domain of BoNT is the cause for the inhibition of the neurotransmitter release and the flaccid paralysis that leads to lethality in botulism. Currently, antidotes are not available to reverse the flaccid paralysis caused by BoNT. In the present study, we have identified three RNA aptamers through SELEX process, which bind strongly to the light chain of type A BoNT (BoNT/A) and inhibit the endopeptidase activity, with IC 50 in low nM range. Inhibition kinetic studies reveal low nM K I and non-competitive nature of their inhibition. Aptamers are unique group of molecules as therapeutics, and this is first report of their development as an antidote against botulism. These data on K I and IC 50 strongly suggest that the aptamers have strong potential as antidotes that can reverse the symptom caused by BoNT/A. KeywordsRNA; aptamer; botulinum neurotoxin; antidote; endopeptidase Botulinum neurotoxins, produced by Clostridia botulinum, are the most toxic substances known to mankind, the cause of the deadly disease, botulism, and can serve as a bioweapon [1,2]. They are also being used as medical therapeutics, treating an array of neuromuscular diseases, and are used for cosmetic applications [3]. Currently, there are seven known serotypes of BoNT, designated as A to G. Of those, type A, B, E are the most common cause for human botulism, and type A is the most potent among the seven serotypes.BoNTs are 150 kDa proteins comprised of three functional domains: the light chains (LCs) of neurotoxins are zinc-endopeptidase, which collectively cleave several proteins involved in synaptic vesicle docking and fusion, and therefore, block the release of acetylcholine. The * Correspondence should be addressed to: Shuowei Cai Department of Chemistry and Biochemistry University of Massachusetts Dartmouth 285 Old Westport Rd North Dartmouth, MA 02747 Phone: 508-999-8807 Fax: 508-999-8451 scai@umassd.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. heavy chain (HC) plays an accessory role of binding to the target nerve cells (through its Cterminus) and the translocation of the LC into the cell cytoplasm (through its N-terminus) [1,3]. NIH Public AccessCurrent therapy for botulism involves respiratory supportive care and the administration of antitoxin. However, to date there is no treatment that can reverse the flaccid muscle paralysis caused by BoNT after the symptom has developed [2][3][4]. Because the toxin has widespread medical therapeutic use...

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Section: Resultsmentioning

confidence: 99%

“…Structures output was chosen as PDB format. Maximum Entropy based Docking (MEDock) was used for molecular docking between aptamer and LCA (http://medock.csie.ntu.edu.tw, [13,14]). No LCA monomer has been crystallized.…”

Section: Methodsmentioning

confidence: 99%

In vitro selection of RNA aptamers that inhibit the activity of type A botulinum neurotoxin

Chang

Blank

Janardhanan

et al. 2010

Biochemical and Biophysical Research Communications

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“…For example, the SLITHER program uses molecular modeling simulations to predict whether a putative substrate molecule may permeate the cavities or channels in a protein structure 71 . In cases where the existence of a channel in a protein is unverified, the MolAxis program can be used to predict whether they exist using computational geometry 72 .…”

Section: Functional Sub-classification Of Transmembrane Protein Classesmentioning

confidence: 99%

Deorphanizing the human transmembrane genome: A landscape of uncharacterized membrane proteins

Babcock

2013

Acta Pharmacol Sin

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The sequencing of the human genome has fueled the last decade of work to functionally characterize genome content. An important subset of genes encodes membrane proteins, which are the targets of many drugs. They reside in lipid bilayers, restricting their endogenous activity to a relatively specialized biochemical environment. Without a reference phenotype, the application of systematic screens to profile candidate membrane proteins is not immediately possible. Bioinformatics has begun to show its effectiveness in focusing the functional characterization of orphan proteins of a particular functional class, such as channels or receptors. Here we discuss integration of experimental and bioinformatics approaches for characterizing the orphan membrane proteome. By analyzing the human genome, a landscape reference for the human transmembrane genome is provided.

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“…D. The second optimum identified by docking with the modified grid. dict the suboptimal binding poses with the scores in the ascending order [86] using an iterative docking approach. SLITHER was first invented to predict the substrate translocation pathway of the membrane transporter, but it was then generalized for proteins with deep pockets inside, e.g., acetylcholinesterase (AChE) and histone deacetylase (HDAC).…”

Section: Extended Application Of Dockingmentioning

confidence: 99%

Accommodating Protein Flexibility for Structure-Based Drug Design

Lin¹

2011

CTMC

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Proper incorporation of protein flexibility for prediction of binding poses and affinities of small compounds has attracted increasing attention recently in computational drug design. Various approaches have been proposed to accommodate protein flexibility in the prediction of binding modes and the binding free energy of ligands in an efficient manner. In this review, the significance of incorporating protein flexibility is discussed from the structural biophysical point of view, and then various approaches of generating protein conformation ensembles, as well as their successes and limitations, are introduced and compared. Special emphasis is on how to generate a proper ensemble of conformation for a specific purpose, as well as the computational efficiency of various approaches. Different searching algorithms for the prediction of optimal binding poses of ligands, which are the core engines of docking programs, are accounted for. Scoring functions for evaluation of protein-ligand complexes are compared. Two end-point methods of free energy calculation, Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and the Linear Interaction Energy (LIE) method, are briefly reviewed. Finally, we also provide an example for the extension of the conventional protein-ligand docking algorithm for prediction of multiple binding sites and ligand translocation pathways.

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SLITHER: a web server for generating contiguous conformations of substrate molecules entering into deep active sites of proteins or migrating through channels in membrane transporters

Cited by 32 publications

References 25 publications

In vitro selection of RNA aptamers that inhibit the activity of type A botulinum neurotoxin

In vitro selection of RNA aptamers that inhibit the activity of type A botulinum neurotoxin

Deorphanizing the human transmembrane genome: A landscape of uncharacterized membrane proteins

Accommodating Protein Flexibility for Structure-Based Drug Design

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