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Douglas R. Houston

Bio: Douglas R. Houston is an academic researcher from University of Edinburgh. The author has contributed to research in topics: Chitinase & Virtual screening. The author has an hindex of 23, co-authored 46 publications receiving 1873 citations. Previous affiliations of Douglas R. Houston include University of Dundee & McGill University.

Papers
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Journal ArticleDOI
TL;DR: Binding of CBP21 to chitin seems to be mediated primarily by conserved, solvent-exposed, polar side chains, as shown by 3–8-fold increases in the apparent binding constant.

267 citations

Journal ArticleDOI
TL;DR: The crystal structure of the human chitotriosidase and complexes with a chitooligosaccharide and allosamidin reveal an elongated active site cleft, compatible with the binding of long chitin polymers, and explain the inactivation of the enzyme through an inherited genetic deficiency.

199 citations

Journal ArticleDOI
TL;DR: This work presents a relatively straightforward method for improving the probability of identifying accurately docked poses, similar in concept to consensus scoring schemes, but combines information about predicted binding modes rather than predicted binding affinities.
Abstract: Structure-based virtual screening relies on scoring the predicted binding modes of compounds docked into the target. Because the accuracy of this scoring relies on the accuracy of the docking, methods that increase docking accuracy are valuable. Here, we present a relatively straightforward method for improving the probability of identifying accurately docked poses. The method is similar in concept to consensus scoring schemes, which have been shown to increase ranking power and thus hit rates, but combines information about predicted binding modes rather than predicted binding affinities. The pose prediction success rate of each docking program alone was found in this trial to be 55% for Autodock, 58% for DOCK, and 64% for Vina. By using more than one docking program to predict the binding pose, correct poses were identified in 82% or more of cases, a significant improvement. In a virtual screen, these more reliably posed compounds can be preferentially advanced to subsequent scoring stages to improve hi...

185 citations

Journal ArticleDOI
TL;DR: Four new CI-4 derivatives are presented in complex with chitinase B from Serratia marcescens, providing further insight into the mechanism of inhibition of chitInases by cyclic dipeptides as well as providing a new scaffold for chit inase inhibitor design.
Abstract: Family 18 chitinases play an essential role in a range of pathogens and pests. Several inhibitors are known, including the potent inhibitors argadin and allosamidin, and the structures of these in complex with chitinases have been elucidated. Recent structural analysis has revealed that CI-4 [cyclo-(L-Arg-D-Pro)] inhibits family 18 chitinases by mimicking the structure of the proposed reaction intermediate. Here we report the high-resolution structures of four new CI-4 derivatives, cyclo-(L-Arg-L-Pro), cyclo-(Gly-L-Pro), cyclo-(L-His-L-Pro), and cyclo-(L-Tyr-L-Pro), in complex with a family 18 chitinase. In addition, details of enzyme inhibition and in vivo activity against Saccharomyces cerevisiae are presented. The structures reveal that the common cyclo-(Gly-Pro) substructure is sufficient for binding, allowing modification of the side chain of the nonproline residue. This suggests that design of cyclic dipeptides with a view to increasing inhibition of family 18 chitinases should be possible through relatively accessible chemistry. The derivatives presented here in complex with chitinase B from Serratia marcescens provide further insight into the mechanism of inhibition of chitinases by cyclic dipeptides as well as providing a new scaffold for chitinase inhibitor design.

148 citations

Journal ArticleDOI
TL;DR: It is shown that HCGP39 is able to bind chitooligosaccharides with micromolar affinity, and this protein could be a lectin that binds chitin-like oligOSaccharide ligands and possibly plays a role in innate responses to chitinous pathogens, such as fungi and nematodes.

139 citations


Cited by
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
TL;DR: This Review suggests a new grouping of macrophages based on three different homeostatic activities — host defence, wound healing and immune regulation, and proposes that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation.
Abstract: Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

7,384 citations

Journal ArticleDOI
TL;DR: The small-molecule topology generator PRODRG is described, which takes input from existing coordinates or various two-dimensional formats and automatically generates coordinates and molecular topologies suitable for X-ray refinement of protein-ligand complexes.
Abstract: The small-molecule topology generator PRODRG is described, which takes input from existing coordinates or various two-dimensional formats and automatically generates coordinates and molecular topologies suitable for X-ray refinement of protein–ligand complexes. Test results are described for automatic generation of topologies followed by energy minimization for a subset of compounds from the Cambridge Structural Database, which shows that, within the limits of the empirical GROMOS87 force field used, structures with good geometries are generated. X-ray refinement in X-­PLOR/CNS, REFMAC and SHELX using PRODRG-generated topologies produces results comparable to refinement with topologies from the standard libraries. However, tests with distorted starting coordinates show that PRODRG topologies perform better, both in terms of ligand geometry and of crystallographic R factors.

4,543 citations

Journal ArticleDOI
TL;DR: This paper comprehensively reviews the lignocellulosic wastes to bioethanol process with a focus on pretreatment methods, their mechanisms, advantages and disadvantages as well as the combinations of different pretreatment technologies.
Abstract: Pretreatment technologies are aimed to increase enzyme accessibility to biomass and yields of fermentable sugars. In general, pretreatment methods fall into four different categories including physical, chemical, physico-chemical, and biological. This paper comprehensively reviews the lignocellulosic wastes to bioethanol process with a focus on pretreatment methods, their mechanisms, advantages and disadvantages as well as the combinations of different pretreatment technologies. Moreover, the new advances in plant “omics” and genetic engineering approaches to increase cellulose composition, reduce cellulose crystallinity, produce hydrolases and protein modules disrupting plant cell wall substrates, and modify lignin structure in plants have also been expansively presented.

1,059 citations

Journal ArticleDOI
08 Oct 2010-Science
TL;DR: An enzyme is described that acts on the surface of crystalline chitin, where it introduces chain breaks and generates oxidized chain ends, thus promoting further degradation by chit inases, demonstrating the existence of a hitherto unknown enzyme activity.
Abstract: Efficient enzymatic conversion of crystalline polysaccharides is crucial for an economically and environmentally sustainable bioeconomy but remains unfavorably inefficient. We describe an enzyme that acts on the surface of crystalline chitin, where it introduces chain breaks and generates oxidized chain ends, thus promoting further degradation by chitinases. This enzymatic activity was discovered and further characterized by using mass spectrometry and chromatographic separation methods to detect oxidized products generated in the absence or presence of H 2 18 O or 18 O 2 . There are strong indications that similar enzymes exist that work on cellulose. Our findings not only demonstrate the existence of a hitherto unknown enzyme activity but also provide new avenues toward more efficient enzymatic conversion of biomass.

1,050 citations