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Schematic representations of chemical structures of fatty acids (a) butyric acid, (b) lauric acid, (c) myristic acid, (d) stearic acid and (e) truncated mycolic acid. The numbering schemes are also indicated.
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Short peptidoglycan recognition protein (PGRP-S) is a member of the mammalian innate immune system. PGRP-S from Camelus dromedarius (CPGRP-S) has been shown to bind to lipopolysaccharide (LPS), lipoteichoic acid (LTA) and peptidoglycan (PGN). Its structure consists of four molecules A, B, C and D with ligand binding clefts situated at A-B and C-D c...
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... results of binding studies, the complexes of CPGRP-S were prepared with several fatty acids by incubating the protein at protein: fatty acid concentrations of 1:10 M ratios. The complexes of the protein with five fatty acids, (a) butyric acid, (BA), (b) lauric acid, (LA), (c) myristic acid, (MA), (d) stearic acid (SA) and (e) mycolic acid (MC) (Fig. 1) were crystallized separately and their three-dimensional structures were determined. The flow cytometric and ELISA studies were carried out to evaluate the pro- ductions of cytokines by cultured peripheral blood mononuclear cells (PBMCs) for different doses of mycolic acid. The results showed that the levels of TNF-a and IFN-c enhanced ...
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... structure determinations of the complexes of CPGRP-S with butyric acid (Fig. 1a), lauric acid (Fig. 1b), myristic acid (Fig. 1c), stearic acid (Fig. 1d) and mycolic acid (Fig. 1e) have revealed that all the five compounds bound to CPGRP-S at the same site which is located at the A-B contact (Fig. 5). The forcep-like fatty acid binding cleft in CPGRP-S is formed essentially by the association of a-helices, a2 from ...
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... structure determinations of the complexes of CPGRP-S with butyric acid (Fig. 1a), lauric acid (Fig. 1b), myristic acid (Fig. 1c), stearic acid (Fig. 1d) and mycolic acid (Fig. 1e) have revealed that all the five compounds bound to CPGRP-S at the same site which is located at the A-B contact (Fig. 5). The forcep-like fatty acid binding cleft in CPGRP-S is formed essentially by the association of a-helices, a2 from molecules A (Aa2) and B ...
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... structure determinations of the complexes of CPGRP-S with butyric acid (Fig. 1a), lauric acid (Fig. 1b), myristic acid (Fig. 1c), stearic acid (Fig. 1d) and mycolic acid (Fig. 1e) have revealed that all the five compounds bound to CPGRP-S at the same site which is located at the A-B contact (Fig. 5). The forcep-like fatty acid binding cleft in CPGRP-S is formed essentially by the association of a-helices, a2 from molecules A (Aa2) and B (Ba2) (Fig. 7). The ...
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... structure determinations of the complexes of CPGRP-S with butyric acid (Fig. 1a), lauric acid (Fig. 1b), myristic acid (Fig. 1c), stearic acid (Fig. 1d) and mycolic acid (Fig. 1e) have revealed that all the five compounds bound to CPGRP-S at the same site which is located at the A-B contact (Fig. 5). The forcep-like fatty acid binding cleft in CPGRP-S is formed essentially by the association of a-helices, a2 from molecules A (Aa2) and B (Ba2) (Fig. 7). The N-terminal segments that run ...
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... structure determinations of the complexes of CPGRP-S with butyric acid (Fig. 1a), lauric acid (Fig. 1b), myristic acid (Fig. 1c), stearic acid (Fig. 1d) and mycolic acid (Fig. 1e) have revealed that all the five compounds bound to CPGRP-S at the same site which is located at the A-B contact (Fig. 5). The forcep-like fatty acid binding cleft in CPGRP-S is formed essentially by the association of a-helices, a2 from molecules A (Aa2) and B (Ba2) (Fig. 7). The N-terminal segments that run along with a-helices Aa2 ...
Citations
... There are four members in this family including PGRP-short (PGRP-S), PGRP-long (PGRP-L), and PGRP-intermediates (PGRP-Iα and PGRP-Iβ) [6][7][8][9]. All the PGRPs have at least one PGRP-S domain which is responsible for the binding to bacterial cell wall molecules such as PGN, lipopolysaccharide (LPS) [10], lipoteichoic acid (LTA) [11], and mycolic acid (MA) [12]. Thus the cell wall molecules of bacteria are the targets for the recognition by PGRPs. ...
... The structure of one complex of the human PGRP-S domain from PGRP-Iα (Iα-HPGRP-S) is also known [27]. It may be noted that the structures of the complexes of CPGRP-S with fatty acids [10,12] and non-fatty acids [10,25] showed different modes of binding. In order to establish the details of the binding sites in CPGRP-S for fatty acids and non-fatty acids, we have determined a new structure of the complex of CPGRP-S with heptanoic acid. ...
Peptidoglycan recognition proteins (PGRPs) are important components of the innate immune system which provide the first line of defense against invading microbes. There are four members in the family of PGRPs in animals of which PGRP-S is a common domain. It is responsible for the binding to microbial cell wall molecules. In order to understand the mode of binding of PGRP-S to the components of the bacterial cell wall, the structure of the complex of camel PGRP-S (CPGRP-S) with heptanoic acid has been determined at 2.15 Å resolution. The structure determination showed the presence of four crystallographically independent protein molecules which are designated as A, B, C, and D. These four protein molecules associate in the form of two homodimers which are represented as A-B and C-D dimers. The association between molecules A and B gives rise to a shallow cleft on the surface at one end of the dimeric interface. One molecule of heptanoic acid is observed at this binding site in the A-B dimer. The association of C and D molecules results in the formation of a long zig-zag tunnel along with the C-D interface. In the cleft at the C-D interface, three molecules of hydrogen peroxide along with other non-water solvent molecules have been observed. The analysis of the several complexes of CPGRP-S with fatty acids and non-fatty acids such as peptidoglycan, lipopolysaccharide, and lipoteichoic acid shows that the fatty acids bind at the A-B site while non-fatty acids interact through C-D interface.
... The increasing evidences from insects and mammals indicated that PGRPs could function in innate immunity as pattern recognition receptor (PRR), signal regulation molecules and effectors . PGRPs can recognize and bind bacterial PGN (Kang et al., 1998;Yoshida et al., 1996), lipopolysaccharide (LPS), lipoteichoic acid (LTA) and fatty acids (Sharma et al., 2012(Sharma et al., , 2013a(Sharma et al., and 2013b, and then activate the downstream immune responses, such as proPO system (Yoshida et al., 1996), Toll pathway (Michel et al., 2001;Lemaitre and Hoffmann, 2007), the immune deficiency (IMD) and c-Jun N-terminal kinase (JNK) pathway (Steiner, 2004;Choe et al., 2002;Bischoff et al., 2006;Maillet et al., 2008). As signal regulation molecules, PGRPs could negatively regulate the IMD pathway and protect the host from innocuous infection (Bischoff et al., 2006;Basbous et al., 2011). ...
... Though PGRPs were originally described as PGN-binding and recognition proteins, some of them could bind various PAMPs or microbes to play indispensable roles in the innate immune system (Dziarski, 2004). For example, rPGRP-S from B. japonicum could bind Dap-type PGN, Lys-type PGN, chitin, and microorganisms including E. coli, S. aureus and Pichia pastoris (Yao et al., 2012), rCPGRPs from Camelus dromedarius could bind LPS, LTA and fatty acids (Sharma et al., 2012(Sharma et al., , 2013a(Sharma et al., and 2013b, and gcPGRP6 splice variants from C. idella were able to bind microbial PAMPs including Lys-type PGN, DAP-type PGN, GLU, Man, and microorganisms including Streptococcus dysgalactiae, Flavobacterium columnare and S. cerevisiae (Yu et al., 2014). In the present study, both rCgPGRPS2 and rCgPGRPS4 showed high binding affinity to Lys-type PGN and Gram-positive bacteria S. aureus in a dose-dependent manner ( Fig. 6C and D, Fig. 7). ...
... The structure of camel protein (CPGRP-S) 17 was determined using the purified protein samples from the natural source of camel colostrum, while the structure of human protein (HPGRP-S) was obtained using the cloned protein. 18 The binding studies of CPGRP-S with various PAMPs 16,[19][20][21][22][23] have shown high binding affinities and structure determinations of the complexes of CPGRP-S with different fragments of PAMPS 16,[19][20][21][22][23] have revealed the site and mode of bindings. This review presents a brief comparison between monomeric structure of HPGRP-S and dimeric structure of CPGRP-S, and describes the therapeutic implications of the two oligomeric states of PGRP-S from two different sources. ...
... The structure of camel protein (CPGRP-S) 17 was determined using the purified protein samples from the natural source of camel colostrum, while the structure of human protein (HPGRP-S) was obtained using the cloned protein. 18 The binding studies of CPGRP-S with various PAMPs 16,[19][20][21][22][23] have shown high binding affinities and structure determinations of the complexes of CPGRP-S with different fragments of PAMPS 16,[19][20][21][22][23] have revealed the site and mode of bindings. This review presents a brief comparison between monomeric structure of HPGRP-S and dimeric structure of CPGRP-S, and describes the therapeutic implications of the two oligomeric states of PGRP-S from two different sources. ...
Peptidoglycan recognition proteins belong to a broad family of innate immunity molecules. Mammals have four types of peptidoglycan recognition proteins designated as PGRP-S, PGRP-Iα, PGRP-Iβ and PGRP-L. PGRP-S is expressed in the granular polymorphonuclear leucocytes, PGRP-Iα is secreted from liver into blood and PGRP-Iβ, and PGRP-L are expressed in the skin, eyes, salivary glands, throat, tongue, esophagus, stomach and intestine. Peptidoglycan recognition proteins protect the host by carrying out early recognition of invading microorganisms. They contain a common domain known as peptidoglycan recognition domain whose lengths in various PGRPs vary from 165 to 175 residues. PGRP-S consists of a single peptidoglycan recognition domain while PGRP-Iα, PGRP-Iβ and PGRP-L have additional domains. Thus, PGRP-S represents the binding component of peptidoglycan recognition proteins and for understanding the mode of binding of these proteins, structural studies of PGRP-S are essential. So far, two structures of PGRP-S, one from human and another from Camelus dromedarius are available. The structure of human PGRP-S is found to be in monomeric state while the structure of camel PGRP-S consists of two distinct dimers in which dimeric interfaces involve opposite faces of the monomer. The observed monomeric and double dimeric structures of PGRP-S are well correlated tothe differences in amino acid sequences of human and camel proteins. The binding sites in the dimers of camel PGRP-S are located at the contact sites of two molecules, whereas in human PGRP-S, it is supported by the single molecule. As a result, the binding clefts in camel protein are formed more efficiently as compared to the human protein. However, tertiary structures of both camel and human proteins are almost identical, with an average root mean squares shift of 1.2 Å for the backbone atoms. Since the ligand binding clefts in camel protein appear to havebeen evolved with better binding potencies than the human protein, the camel PGRP-S could be exploited for beneficial therapeutic applications against bacterial infections.
... The binding studies of CPGRP-S using SPR were carried out with both ligands, LPS and SA. It has been shown by previous structural studies of binary complexes of CPGRP-S with LPS and SA [9][10][11] that LPS bound to CPGRP-S in the binding Site-1 at the C-D contact while SA was found to bind the protein in the binding Site-2 at the A-B contact [19]. Since the two binding sites were located distantly from each other, the surface plasmon resonance studies were carried out with both ligands separately as well as one after the other. ...
... The molecular mass of the first peak in the elution profile obtained using size exclusion chromatography was estimated based on the void volume. This value was similar to that determined by extrapolating the value of hydrodynamic radii observed using dynamic light scattering of the protein [19]. These values were similar to that derived from the polymeric nature of the structure as indicated by the structure determination [19]. ...
... This value was similar to that determined by extrapolating the value of hydrodynamic radii observed using dynamic light scattering of the protein [19]. These values were similar to that derived from the polymeric nature of the structure as indicated by the structure determination [19]. The previous structural studies have shown that there are two independent ligand binding sites. ...
Peptidoglycan recognition proteins (PGRPs) are part of the innate immune system. The 19 kDa Short PGRP (PGRP-S) is one of the four mammalian PGRPs. The concentration of PGRP-S in camel (CPGRP-S) has been shown to increase considerably during mastitis. The structure of CPGRP-S consists of four protein molecules designated as A, B, C and D forming stable intermolecular contacts, A-B and C-D. The A-B and C-D interfaces are located on the opposite sides of the same monomer leading to the the formation of a linear chain with alternating A-B and C-D contacts. Two ligand binding sites, one at C-D contact and another at A-B contact have been observed. CPGRP-S binds to the components of bacterial cell wall molecules such as lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PGN) from both Gram-positive and Gram-negative bacteria. It also binds to fatty acids including mycolic acid of the Mycobacterium tuberculosis (Mtb). Previous structural studies of binary complexes of CPGRP-S with LPS and stearic acid (SA) have shown that LPS binds to CPGRP-S at C-D contact (Site-1) while SA binds to it at the A-B contact (Site-2). The binding studies using surface plasmon resonance showed that LPS and SA bound to CPGRP-S in the presence of each other. The structure determination of the ternary complex showed that LPS and SA bound to CPGRP-S at Site-1 and Site-2 respectively. LPS formed 13 hydrogen bonds and 159 van der Waals contacts (distances ≤4.2 Å) while SA formed 56 van der Waals contacts. The ELISA test showed that increased levels of productions of pro-inflammatory cytokines TNF-α and IFN-γ due to LPS and SA decreased considerably upon the addition of CPGRP-S.
The short peptidoglycan recognition protein (PGRP-S) of the innate immune system recognizes the invading microbes through binding to their cell wall molecules. In order to understand the mode of binding of PGRP-S to bacterial cell wall molecules, the structure of the complex of camel PGRP-S (CPGRP-S) with hexanoic acid has been determined at 2.07 Å resolution. Previously, we had reported the structures of CPGRP-S in the native unbound state as well as in the complexed forms with the components of various bacterial cell wall molecules such as peptidoglycan (PGN), lipopolysaccharide (LPS), lipoteichoic acid (LTA), mycolic acid (MA) and other fatty acids. These structures revealed that CPGRP-S formed two homodimers which were designated as A-B and CD dimers. It also showed that the fatty acids bind to CPGRP-S in the binding site at the A-B dimer while the non-fatty acids were shown to bind at the interfaces of both A-B and CD dimers. The present structure of the complex of CPGRP-S with hexanoic acid (HA) showed that HA binds to CPGRP-S at the interface of CD dimer. HA was located in the same groove at the CD interface which was occupied by non-fatty acids such as PGN, LPS and LTA and interacts with residues from both C and D molecules. HA is firmly held in the groove with several hydrogen bonds and a number of van der Waals contacts. This is the first structure which reports the binding of a fatty acid in the cleft at the interface of CD dimer.
Peptidoglycan (PGN) is a unique component in the cytoderm of prokaryotes which can be recognized by different pathogen-associated molecular patterns (PAMPs) in eukaryotes, followed by a cascade of immune responses via different pathways. This review outlined the basic structure of PGN, its immunologic functions. The immunomodulation pathways mediated by PGN were elaborated. PGN induces specific immunity through stimulating different cytokine release and Th1/Th2-dominated immune responses during humoral/cellular immune response. The nonspecific immunity activation by PGN involves immunomodulation by different pattern recognition receptors (PRRs) including PGN recognition proteins (PGRPs), nucleotide oligomerization domain (NOD)–like receptors (NLRs), Toll-like receptors (TLRs), and C-type lectin receptors (CLRs). The sources and classification of PGRPs were summarized. In view of the stimulating activities of PGN and its monomers, the potential application of PGN as vaccine or adjuvant was prospected. This review provides systematic information on PGN functionalities from the point of immunoregulation, which might be useful in the deep exploitation of PGN.
Key points.The immunological functions of PGN were illustrated.
Cellular and humoral immunomodulation by PGN were outlined.
The use of PGN as vaccine or adjuvant was prospected.
Gram-positive bacteria are responsible for a broad range of infectious diseases, and the emergency and wide spread of drug-resistant Gram-positive pathogens including MRSA and MRSE has caused great concern throughout the world. 4-Quinolones which are exemplified by fluoroquinolones are mainstays of chemotherapy against various bacterial infections including Gram-positive pathogen infections, and their value and role in the treatment of bacterial infections continues to expand. However, the resistance of Gram-positive organisms to 4-quinolones develops rapidly and spreads widely, making them more and more ineffective. To overcome the resistance and reduce the toxicity, numerous of 4-quinolone derivatives were synthesized and screened for their in vitro and in vivo activities against Gram-positive pathogens, and some of them exhibited excellent potency. This review aims to outlines the recent advances made towards the discovery of 4-quinolone-based derivatives as anti-Gram-positive pathogens agents and the critical aspects of design as well as the structure-activity relationship of these derivatives. The enriched SAR paves the way to the further rational development of 4-quinolones with a unique mechanism of action different from that of the currently used drugs to overcome the resistance, well-tolerated and low toxic profiles.
The emergence and wide-spread of drug-resistant bacteria including multi-drug resistant and pan-drug resistant pathogens which are associated with considerable mortality, represent a significant global health threat. 4-Quinolones which are exemplified by fluoroquinolones are the second largest chemotherapy agents used in clinical practice for the treatment of various bacterial infections. However, the resistance of bacteria to 4-quinolones develops rapidly and spreads widely throughout the world due to the long-term, inappropriate use and even abuse. To overcome the resistance and improve the potency, several strategies have been developed. Amongst them, molecular hybridization, which is based on the incorporation of two or more pharmacophores into a single molecule with a flexible linker, is one of the most practical approaches. This review aims to summarize the recent advances made towards the discovery of 4-quinolone hybrids as potential antibacterial agents as well as their structure-activity relationship (SAR). The enriched SAR may pave the way for the further rational development of 4-quinolone hybrids with excellent potency against both drug-susceptible and drug-resistant bacteria.
Johne's disease or Paratuberculosis has emerged as major infectious disease of animals in general and domestic livestock in particular on global basis. There have been major initiatives in developed countries for the control of this incurable malady of animals and human beings alike (inflammatory bowel disease or Crohn's disease). Disease has not received similar attention due to inherent complexities of disease, diagnosis and control, in resource poor counties around the world. However, the rich genetic diverstiy of the otherwise low productive animal population offers opportunity for the control of Johne's disease and improve per animal productivity. Present review aims to gather and compile information available on genetics or resistance to Johne's disease and its future exploitation by resource poor countries rich in animal diversity. This review will also help to create awareness and share knowledge and experience on prevalence and opportunities for control of Johne's disease in the livestock population to boost per animal productivity among developing and poor countries of the world. Breeding of animals for disease resistance provides good, safe, effective and cheaper way of controlling Johne's disease in animals, with especial reference to domestic livestock of developing and poor countries. Study will help to establish better understanding of the correlation between host cell factors and resistance to MAP infection which may have ultimately help in the control of Johne's disease in future.
