Structural and functional studies of a 50kDa antigenic protein from Salmonella enterica serovar Typhi

Choong, Yee Siew; Lim, Theam Soon; Chew, Ai Lan; Ismail, Asma

doi:10.1016/j.jmgm.2011.01.008

Cited by 11 publications

(12 citation statements)

References 94 publications

(143 reference statements)

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“…To date, comparative modeling is the most successful and accurate method as evolutionarily related proteins usually share a similar structure (sequence identity > 30%) [40,41]. However, searching for homologous proteins is difficult when the sequence identity is low or known as the “twilight-zone”, where the sequence identity falls between 10%–30% [42].…”

Section: Resultsmentioning

confidence: 99%

The Structure and Dynamics of BmR1 Protein from Brugia malayi: In Silico Approaches

Khor

Tye

Lim

et al. 2014

IJMS

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Brugia malayi is a filarial nematode, which causes lymphatic filariasis in humans. In 1995, the disease has been identified by the World Health Organization (WHO) as one of the second leading causes of permanent and long-term disability and thus it is targeted for elimination by year 2020. Therefore, accurate filariasis diagnosis is important for management and elimination programs. A recombinant antigen (BmR1) from the Bm17DIII gene product was used for antibody-based filariasis diagnosis in “Brugia Rapid”. However, the structure and dynamics of BmR1 protein is yet to be elucidated. Here we study the three dimensional structure and dynamics of BmR1 protein using comparative modeling, threading and ab initio protein structure prediction. The best predicted structure obtained via an ab initio method (Rosetta) was further refined and minimized. A total of 5 ns molecular dynamics simulation were performed to investigate the packing of the protein. Here we also identified three epitopes as potential antibody binding sites from the molecular dynamics average structure. The structure and epitopes obtained from this study can be used to design a binder specific against BmR1, thus aiding future development of antigen-based filariasis diagnostics to complement the current diagnostics.

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Section: Resultsmentioning

confidence: 99%

The Structure and Dynamics of BmR1 Protein from Brugia malayi: In Silico Approaches

Khor

Tye

Lim

et al. 2014

IJMS

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“…Another β-OG molecule is identified at the entrance of the periplasmic tunnel, where hexamminecobalt, the potent blocker of TolC and ST50, has also been located 2 25 . Apart from hexamminecobalt, two ions, Na + and K + , were also reported to bind to TolC near the periplasmic entrance based on computer simulations.…”

Section: Resultsmentioning

confidence: 99%

“…Even in a developed country, such as the USA, approximately 6,000 new cases of typhoid fever occur each year. Currently, the principal method to diagnose typhoid fever is TYPHIDOT, a rapid immunoassay test to detect IgM and IgG antibodies against the outer-membrane protein ST50 of S. Typhi 2 3 .…”

mentioning

confidence: 99%

Crystal structure of an antigenic outer-membrane protein from Salmonella Typhi suggests a potential antigenic loop and an efflux mechanism

Guan

Yoshimura

Chuankhayan

et al. 2015

Sci Rep

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ST50, an outer-membrane component of the multi-drug efflux system from Salmonella enterica serovar Typhi, is an obligatory diagnostic antigen for typhoid fever. ST50 is an excellent and unique diagnostic antigen with 95% specificity and 90% sensitivity and is used in the commercial diagnosis test kit (TYPHIDOTTM). The crystal structure of ST50 at a resolution of 2.98 Å reveals a trimer that forms an α-helical tunnel and a β-barrel transmembrane channel traversing the periplasmic space and outer membrane. Structural investigations suggest significant conformational variations in the extracellular loop regions, especially extracellular loop 2. This is the location of the most plausible antibody-binding domain that could be used to target the design of new antigenic epitopes for the development of better diagnostics or drugs for the treatment of typhoid fever. A molecule of the detergent n-octyl-β-D-glucoside is observed in the D-cage, which comprises three sets of Asp361 and Asp371 residues at the periplasmic entrance. These structural insights suggest a possible substrate transport mechanism in which the substrate first binds at the periplasmic entrance of ST50 and subsequently, via iris-like structural movements to open the periplasmic end, penetrates the periplasmic domain for efflux pumping of molecules, including poisonous metabolites or xenobiotics, for excretion outside the pathogen.

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“…A comparative model of the S. typhi TolC protein [5] was used as the starting structure in this study. Polar hydrogens were added using the program Reduce [32].…”

Section: Simulation Setupmentioning

confidence: 99%

“…An outer membrane protein (OMP) was demonstrated to be antigenic for S. typhi and subsequently developed into TYPHIDOT (Reszon Diagnostics International, Subang Jaya, Selangor, Malaysia), a rapid dot enzyme immunoassay test for typhoid fever [3,4]. The protein was shown to be a homologue of Escherichia coli TolC efflux pump through comparative modeling [5]. TolC and its homologues, including Vibrio cholerae VceC [6] and Pseudomonas aeruginosa OprM [7], form tripartite pumps that are involved in the type I secretion system, exporting enzymes, toxins, small noxious agents, heavy metals and antibiotics from the cell [8], thus contributing to multidrug resistance in a number of Gram-negative bacteria pathogens.…”

Section: Introductionmentioning

confidence: 99%

Assembly and stability of Salmonella enterica ser. Typhi TolC protein in POPE and DMPE

et al. 2014

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In this work we assessed the suitability of two different lipid membranes for the simulation of a TolC protein from Salmonella enterica serovar Typhi. The TolC protein family is found in many pathogenic Gram-negative bacteria including Vibrio cholera and Pseudomonas aeruginosa and acts as an outer membrane channel for expulsion of drug and toxin from the cell. In S. typhi, the causative agent for typhoid fever, the TolC outer membrane protein is an antigen for the pathogen. The lipid environment is an important modulator of membrane protein structure and function. We evaluated the conformation of the TolC protein in the presence of DMPE and POPE bilayers using molecular dynamics simulation. The S. typhi TolC protein exhibited similar conformational dynamics to TolC and its homologues. Conformational flexibility of the protein is seen in the C-terminal, extracellular loops, and α-helical region. Despite differences in the two lipids, significant similarities in the motion of the protein in POPE and DMPE were observed, including the rotational motion of the C-terminal residues and the partially open extracellular loops. However, analysis of the trajectories demonstrated effects of hydrophobic matching of the TolC protein in the membrane, particularly in the lengthening of the lipids and subtle movements of the protein's β-barrel towards the lower leaflet in DMPE. The study exhibited the use of molecular dynamics simulation in revealing the differential effect of membrane proteins and lipids on each other. In this study, POPE is potentially a more suitable model for future simulation of the S. typhi TolC protein.

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Structural and functional studies of a 50kDa antigenic protein from Salmonella enterica serovar Typhi

Cited by 11 publications

References 94 publications

The Structure and Dynamics of BmR1 Protein from Brugia malayi: In Silico Approaches

The Structure and Dynamics of BmR1 Protein from Brugia malayi: In Silico Approaches

Crystal structure of an antigenic outer-membrane protein from Salmonella Typhi suggests a potential antigenic loop and an efflux mechanism

Assembly and stability of Salmonella enterica ser. Typhi TolC protein in POPE and DMPE

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