Structural genomics for drug design against the pathogen <i>Coxiella burnetii</i>

Franklin, Matthew C.; Cheung, Jonah; Rudolph, M.; Burshteyn, F.; Cassidy, M.; Gary, E.; Hillerich, B.; Yao, Zhendan; Carlier, Paul R.; Totrov, Maxim; Love, J.

doi:10.1002/prot.24841

Cited by 79 publications

(77 citation statements)

References 71 publications

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“…A dimerization mode similar to that of AtAER is prevented in ceQORH by the orientation of the α-helix Pro254-Met267. Analysis of QOR from C. Burnetii (PDB entry: 3TQH) (Franklin et al, 2015) bound to NADPH, which is also a monomeric QOR supports this explanation as an α-helix equivalent to the ceQORH Pro254-Met267 α-helix is also observed. As ceQORH is associated to the inner membrane of chloroplast envelope (Miras et al, 2007), a monomeric state could increase its catalytic efficiency (higher mobility, better dispersion on the membrane surface) and might have been selected during evolution as this would favor the detoxification rate.…”

Section: Discussionmentioning

confidence: 92%

“…When monomers are superimposed the values of rmsd go from 1.42 Å (comparison with the QOR from C. burnetii , PDB entry: 3TQH) (Franklin et al, 2015) to 2.65 Å (comparison with a putative NADPH quinone reductase from Mesorhizobium loti , PDB entry: 3PI7). The sequence identity based on structure comparison goes from 20 to 32%.…”

Section: Resultsmentioning

confidence: 99%

“…The structure of the QOR from Coxiella burnetii (PDB entry: 3TQH) (Franklin et al, 2015) was used as model and modified based on sequence alignment with ceQORH using CHAINSAW (Stein, 2008) from CCP4 to calculate the phases for the data of ceQORH-13-KOTE. The other structures were solved using the monomer of ceQORH-13-KOTE as search model for molecular replacement.…”

Section: Methodsmentioning

confidence: 99%

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Crystal Structure of the Chloroplastic Oxoene Reductase ceQORH from Arabidopsis thaliana

et al. 2017

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Enzymatic and non-enzymatic peroxidation of polyunsaturated fatty acids give rise to accumulation of aldehydes, ketones, and α,β-unsaturated carbonyls of various lengths, known as oxylipins. Oxylipins with α,β-unsaturated carbonyls are reactive electrophile species and are toxic. Cells have evolved several mechanisms to scavenge reactive electrophile oxylipins and decrease their reactivity such as by coupling with glutathione, or by reduction using NAD(P)H-dependent reductases and dehydrogenases of various substrate specificities. Plant cell chloroplasts produce reactive electrophile oxylipins named γ-ketols downstream of enzymatic lipid peroxidation. The chloroplast envelope quinone oxidoreductase homolog (ceQORH) from Arabidopsis thaliana was previously shown to reduce the reactive double bond of γ-ketols. In marked difference with its cytosolic homolog alkenal reductase (AtAER) that displays a high activity toward the ketodiene 13-oxo-9(Z),11(E)-octadecadienoic acid (13-KODE) and the ketotriene 13-oxo-9(Z), 11(E), 15(Z)-octadecatrienoic acid (13-KOTE), ceQORH binds, but does not reduce, 13-KODE and 13-KOTE. Crystal structures of apo-ceQORH and ceQORH bound to 13-KOTE or to NADP+ and 13-KOTE have been solved showing a large ligand binding site, also observed in the structure of the cytosolic alkenal/one reductase. Positioning of the α,β-unsaturated carbonyl of 13-KOTE in ceQORH-NADP+-13-KOTE, far away from the NADP+ nicotinamide ring, provides a rational for the absence of activity with the ketodienes and ketotrienes. ceQORH is a monomeric enzyme in solution whereas other enzymes from the quinone oxidoreductase family are stable dimers and a structural explanation of this difference is proposed. A possible in vivo role of ketodienes and ketotrienes binding to ceQORH is also discussed.

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Crystal Structure of the Chloroplastic Oxoene Reductase ceQORH from Arabidopsis thaliana

et al. 2017

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“…GMP synthase structures are now available for other bacterium (Coxiella burnetii (40) and Thermus thermophiles (PDB codes 2YWB and 2YWC)), archaea (Pyrococcus horikoshii (41)), and two eukaryotes (Plasmodium falciparum (42), Homo sapiens (43)); all contain ATPPPase, GATase, and dimerization domains.…”

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confidence: 99%

GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans

Chitty

Tatzenko

Williams

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuOver the last four decades the HIV pandemic and advances in medical treatments that also cause immunosuppression have produced an ever-growing cohort of individuals susceptible to opportunistic pathogens. Of these, AIDS patients are particularly vulnerable to infection by the encapsulated yeast Cryptococcus neoformans. Most commonly found in the environment in purine-rich bird guano, C. neoformans experiences a drastic change in nutrient availability during host infection, ultimately disseminating to colonize the purine-poor central nervous system. Investigating the consequences of this challenge, we have characterized C. neoformans GMP synthase, the second enzyme in the guanylate branch of de novo purine biosynthesis. We show that in the absence of GMP synthase, C. neoformans becomes a guanine auxotroph, the production of key virulence factors is compromised, and the ability to infect nematodes and mice is abolished. Activity assays performed using recombinant protein unveiled differences in substrate binding between the C. neoformans and human enzymes, with structural insights into these kinetic differences acquired via homology modeling. Collectively, these data highlight the potential of GMP synthase to be exploited in the development of new therapeutic agents for the treatment of disseminated, life-threatening fungal infections.In the past four decades there has been a dramatic escalation in the number of immunocompromised individuals (1). Although many of these are due to advances in immunosuppressive and chemotherapeutic technologies, the largest cohort is a direct result of the AIDS pandemic. Foreshadowed in 1981 with the occurrence of opportunistic Pneumocystis or human herpesvirus 8 infections in previously healthy individuals in Los Angeles (2, 3), AIDS and the lentivirus causing the disease soon gained broad public awareness (4 -6). With the advent of commercial blood testing, national blood bank screening programs were commenced in an effort to slow the spread of this emerging pandemic (7), and in 1987 the first treatment, zidovudine, marked what was thought to be an end to the crisis (8, 9). It was not, as was hoped, a miracle drug; the spread of AIDS continued across the globe and is now believed to have infected over 70 million people and killed 55 million to date (10).Since the discovery of the very first patients identified with Pneumocystis pneumonia, opportunistic fungal pathogens have been tightly linked with the AIDS pandemic. One of the key fungi often encountered in this context is Cryptococcus neoformans, a basidiomycete yeast responsible for cryptococcosis and a major cause of AIDS-related mortality (11). Most commonly found associated with purine-rich bird guano, spores or desiccated yeast cells from this environmental niche are inhaled into the lungs where, in an immunocompromised individual, the fungus can disseminate to the purine-poor central nervous system to cause meningoencephalitis.The fundamental treatment for cryptococcosis has not changed significantly ...

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“…Certain methods have been utilized for R-gene mining, including experiment methods like protein/gene fusion56, sequence assembly47, sequence alignment/similarity89, and structure-based approach1011, etc. Because of biological mining methods are time-consuming and expensive for genome identification, machine learning methods are developed much more efficiently in classification and prediction of R-gene.…”

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confidence: 99%

Resistance gene identification from Larimichthys crocea with machine learning techniques

Cai

Liao

et al. 2016

Sci Rep

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The research on resistance genes (R-gene) plays a vital role in bioinformatics as it has the capability of coping with adverse changes in the external environment, which can form the corresponding resistance protein by transcription and translation. It is meaningful to identify and predict R-gene of Larimichthys crocea (L.Crocea). It is friendly for breeding and the marine environment as well. Large amounts of L.Crocea’s immune mechanisms have been explored by biological methods. However, much about them is still unclear. In order to break the limited understanding of the L.Crocea’s immune mechanisms and to detect new R-gene and R-gene-like genes, this paper came up with a more useful combination prediction method, which is to extract and classify the feature of available genomic data by machine learning. The effectiveness of feature extraction and classification methods to identify potential novel R-gene was evaluated, and different statistical analyzes were utilized to explore the reliability of prediction method, which can help us further understand the immune mechanisms of L.Crocea against pathogens. In this paper, a webserver called LCRG-Pred is available at http://server.malab.cn/rg_lc/.

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Structural genomics for drug design against the pathogen Coxiella burnetii

Cited by 79 publications

References 71 publications

Crystal Structure of the Chloroplastic Oxoene Reductase ceQORH from Arabidopsis thaliana

Crystal Structure of the Chloroplastic Oxoene Reductase ceQORH from Arabidopsis thaliana

GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans

Resistance gene identification from Larimichthys crocea with machine learning techniques

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