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The sequence-specific recognition mechanism of single-stranded RNA (ssRNA) motif by Gallus TLR21 (gTLR21). A, The sequence and structure of ssRNA. B, C, The ssRNA could form a stem-loop-like structure so that its 5 ′ and 3 ′ arms mainly fit along the inner concave surface formed by the C-and N-terminal ends of the gTLR21 ECD, respectively. D, The bases A2054 and G2056-2058 of the ssRNA can bind to the interaction surface surrounded by residues located in LRR17-22 via potential π-cation interaction, hydrogen bonds, and salt bridges. E, The backbone phosphates of base A2059 is recognized by Lys49 and form hydrogen bonds with Asp47 and Arg55, whereas the base A2060 interfaces with Arg55, Glu653, and Arg701 via salt bridges. F, The base G2061 in the ssRNA motif interfaces with Glu653-Asn654 of LRR24, whereas Arg678 of LRR25 and Arg701 and Lys702 of LRR26 contribute to a combined interface with the base A2062 via multiple intermolecular forces. G, Tyr82 of LRR1 and Tyr106 of LRR2 are also involved in maintaining the structure of gTLR21-ssRNA complex via hydrogen bonds. The side chains of gTLR21 are colored blue (in the ball-and-stick model), and the bases of ssRNA motif are green. H-bonds, π-cation interactions, and salt bridges are indicated by blue, yellow, and wheat dashed lines, respectively
Source publication
Toll-like receptors (TLRs) are an important part of the innate immune system, acting as a first line of defense against many invading pathogens. The ligand known to bind Gallus toll-like receptor 21 (gTLR21) is the unmethylated cytosine phosphate guanine dideoxy nucleotide motif; however, the evolutionary characteristics and structural biology of g...
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... have also investigated the potential binding mechanism of gTLR21 with ssRNA. The ssRNA molecule ( Figure 6A) likely fits along the inner concave surface of gTLR21, with its 5 ′ and 3 ′ arms binding to the C- and N-terminal ends of gTLR21 ECD ( Figure 6B), respectively. This is consistent with how ssRNA molecules bind TLR13, except for opposite orientation of binding of TLR3-double-stranded RNA complex. ...
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... have also investigated the potential binding mechanism of gTLR21 with ssRNA. The ssRNA molecule ( Figure 6A) likely fits along the inner concave surface of gTLR21, with its 5 ′ and 3 ′ arms binding to the C- and N-terminal ends of gTLR21 ECD ( Figure 6B), respectively. This is consistent with how ssRNA molecules bind TLR13, except for opposite orientation of binding of TLR3-double-stranded RNA complex. ...
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... side chains of gTLR21 are colored blue (in the ball-and-stick model), and the bases of ssRNA motif are green. H-bonds, π-cation interactions, and salt bridges are indicated by blue, yellow, and wheat dashed lines, respectively structure that is highly similar to those observed in TLR13-ssRNA complex ( Figure 6C); the stem-loop-like structure is also essential for TLR13 recognition of ssRNA. 9,41 Our structural biology analysis also strongly indicates that the predicted interaction surface is surrounded by the LRRNT, LRR1-2, LRR17-22, and LRR24-26 motifs of the gTLR21 ECD to fix the ssRNA in position. ...
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... the bases G2056 and G2057 may potentially form salt bridges with Asp522 and Arg547, respectively, in the combined domain ( Figure 6D). With the extension of the ssRNA motif, A2059 is recognized by Asp47, Arg55, and Lys49 via multiple intermolecular interactions. ...
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... the extension of the ssRNA motif, A2059 is recognized by Asp47, Arg55, and Lys49 via multiple intermolecular interactions. It is clear that the backbone phosphates of the base A2060 are recognized by Arg55, Glu653, and Arg701 ( Figure 6E). The Glu653 toAsn654 of LRR24, Arg678 of LRR25, and Arg701 and Lys702 of LRR26 also contribute to the maintenance of this structure via different intermolecular forces ( Figure 6F). ...
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... is clear that the backbone phosphates of the base A2060 are recognized by Arg55, Glu653, and Arg701 ( Figure 6E). The Glu653 toAsn654 of LRR24, Arg678 of LRR25, and Arg701 and Lys702 of LRR26 also contribute to the maintenance of this structure via different intermolecular forces ( Figure 6F). The docking results indicate that Tyr82 of LRR1 and Tyr106 of LRR2 also devote to bind to the bases of 3 ′ arms of the ssRNA motif via hydrogen bonds ( Figure 6G). ...
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... Glu653 toAsn654 of LRR24, Arg678 of LRR25, and Arg701 and Lys702 of LRR26 also contribute to the maintenance of this structure via different intermolecular forces ( Figure 6F). The docking results indicate that Tyr82 of LRR1 and Tyr106 of LRR2 also devote to bind to the bases of 3 ′ arms of the ssRNA motif via hydrogen bonds ( Figure 6G). Recently, a series of studies has demonstrated that Mus TLR13 is a receptor for the vesicular stomatitis virus 42 and could detect sequence-specifc areas of 23S ribosomal RNA from bacteria. ...
Citations
... Training profiles for HMMer were built using a fasta alignment of known TLR toll-interleukin-1 receptor (TIR) domains from humans and representative vertebrates (Thompson et al. 2021). TIR domains were chosen for queries as these regions have been shown to be more well conserved and less variable than other TLR regions (Roach et al. 2005;Wu et al. 2018). Moreover, TIR domains exhibit higher levels of sequence conservation than TLR ectodomains which are characterized by leucine-rich repeats that are found in over 6000 other proteins on the Pfam database (Matsushima et al. 2007). ...
Since its initial discovery over 50 years ago, understanding the evolution of the vertebrate RAG- mediated adaptive immune response has been a major area of research focus for comparative geneticists. However, how the evolutionary novelty of an adaptive immune response impacted the diversity of receptors associated with the innate immune response has received considerably less attention until recently. Here, we investigate the diversification of vertebrate toll-like receptors (TLRs), one of the most ancient and well conserved innate immune receptor families found across the Tree of Life, integrating genomic data that represent all major vertebrate lineages with new transcriptomic data from Polypteriformes, the earliest diverging ray-finned fish lineage. Our analyses reveal TLR sequences that reflect the 6 major TLR subfamilies, TLR1, TLR3, TLR4, TLR5, TLR7, and TLR11, and also currently unnamed, yet phylogenetically distinct TLR clades. We additionally recover evidence for a pulse of gene gain coincident with the rise of the RAG-mediated adaptive immune response in jawed vertebrates, followed by a period of rapid gene loss during the Cretaceous. These gene losses are primarily concentrated in marine teleost fish and synchronous with the mid Cretaceous anoxic event, a period of rapid extinction for marine species. Finally, we reveal a mismatch between phylogenetic placement and gene nomenclature for up to 50% of TLRs found in clades such as ray-finned fishes, cyclostomes, amphibians, and elasmobranchs. Collectively, these results provide an unparalleled perspective of TLR diversity and offer a ready framework for testing gene annotations in non-model species.
... Training profiles for HMMer were built using a fasta alignment of known TLR toll-interleukin-1 receptor (TIR) domains from humans and representative vertebrates (Thompson et al. 2021). TIR domains were chosen for queries as these regions have been shown to be more well conserved and less variable than other TLR regions (Roach et al. 2005;Wu et al. 2018). Moreover, TIR domains exhibit higher levels of sequence conservation than TLR ectodomains which are characterized by leucine rich repeats that are found in over 6000 other proteins on the Pfam database (Matsushima et al. 2007). ...
Since its initial discovery over 50 years ago, understanding the evolution of the vertebrate adaptive immune response has been a major area of research focus for comparative geneticists. However, how the evolutionary novelty of an adaptive immune response impacted the diversity of receptors associated with the innate immune response has received considerably less attention until recently. Here we investigate the diversification of vertebrate Toll-like receptors (TLRs), one of the most ancient and well conserved innate immune receptor families found across the Tree of Life, integrating genomic data that represent all major vertebrate lineages with new transcriptomic data from Polypteriformes, the earliest diverging ray-finned fish lineage. Our analyses reveal TLR sequences that reflect the 6 major TLR subfamilies, TLR1, TLR3, TLR4, TLR5, TLR7, and TLR11, and also currently unnamed, yet phylogenetically distinct TLR clades. We additionally recover evidence for a pulse of gene gain coincident with the rise of the adaptive immune response in jawed vertebrates, followed by a period of rapid gene loss during the Cretaceous. These gene losses are primarily concentrated in marine teleost fish and synchronous with the mid Cretaceous anoxic event, a period of rapid extinction for marine species. Finally, we reveal a mismatch between phylogenetic placement and gene nomenclature for up to 50% of TLRs found in clades such as ray-finned fishes, cyclostomes, amphibians, and elasmobranchs. Collectively these results provide an unparalleled perspective of TLR diversity, and offer a ready framework for testing gene annotations in non-model species.
... Duck TLR21 sequence was submitted to NCBI database under the accession number MT081574. Signal peptide, leucine-rich repeats (LRRs), N-terminal LRR (LRR-NT), C-terminal LRR (LRR-CT), transmembrane domain (TM), and Toll/interleukin receptor (TIR) domain are assigned based on previous reports on chicken TLR21 [39]. The boxed regions are box1, box2, and box3 in the TIR domain. ...
... The TLR11 family contains two subfamilies, TLRs 11-13 and TLRs 20-22. TLR21 is an ortholog of mouse TLR13 [39,40]. When searching NCBI nucleotide databases, putative sequences for the TLR13 of avian species including wild turkey, helmeted guinea fowl, great tit, Atlantic canary, and white-throated sparrow were identified, but none of their TLR21s were found. ...
CpG-oligodeoxynucleotides (CpG-ODNs) mimicking the function of microbial CpG-dideoxynucleotides containing DNA (CpG-DNA) are potent immune stimuli. The immunostimulatory activity and the species-specific activities of a CpG-ODN depend on its nucleotide sequence properties, including CpG-hexamer motif types, spacing between motifs, nucleotide sequence, and length. Toll-like receptor (TLR) 9 is the cellular receptor for CpG-ODNs in mammalian species, while TLR21 is the receptor in avian species. Mammalian cells lack TLR21, and avian cells lack TLR9; however, both TLRs are expressed in fish cells. While nucleotide sequence properties required for a CpG-ODN to strongly activate mammalian TLR9 and its species-specific activities to different mammalian TLR9s are better studied, CpG-ODN activation of TLR21 is not yet well investigated. Here we characterized chicken and duck TLR21s and investigated their activation by CpG-ODNs. Chicken and duck TLR21s contain 972 and 976 amino acid residues, respectively, and differ from TLR9s as they do not have an undefined region in their ectodomain. Cell-based TLR21 activation assays were established to investigate TLR21 activation by different CpG-ODNs. Unlike grouper TLR21, which was preferentially activated by CpG-ODN with a GTCGTT hexamer motif, chicken and duck TLR21s do not distinguish among different CpG-hexamer motifs. Additionally, these two poultry TLR21s were activated by CpG-ODNs with lengths ranging from 15 to 31 nucleotides and with different spacing between CpG-hexamer motifs. These suggested that compared to mammalian TLR9 and grouper TLR21, chicken and duck TLR21s have a broad CpG-ODN sequence recognition profile. Thus, they could also recognize a wide array of DNA-associated molecular patterns from microbes. Moreover, CpG-ODNs are being investigated as antimicrobial agents and as vaccine adjuvants for different species. This study revealed that there are more optimized CpG-ODNs that can be used in poultry farming as anti-infection agents compared to CpG-ODN choices available for other species.
... TLR are a family of conserved trans-membrane protein family receptors that play a role in the recognition of preserved molecular motifs. In general, the structure of TLRs consists of the Nterminal and C-terminal domains domain, leucine-rich repeats (LRRs) and the highly conserved cytoplasmic Toll / IL-1 receptor (TIR) domain (Chen et al., 2013;Wu et al., 2018). Leucine-rich repeats (LRRs) support specific interactions between conserved membrane proteins (MAMP) and the TLR family. ...
In today's world, milk has an important place in meeting animal protein needs. The milk in consumption is mostly obtained from breeding (high yielding and healthy) cows. In the Aegean region, cattle breeding is carried out by preferring Holstein breed mostly in different sized and semi-closed dairy farms. In Mugla province, there exists totally 120 thousand milking cows. However, ‘traditional breeding’ (inadequate maintenance-feeding) methods are mostly used in dairy enterprises. Therefore, the desired level of animal welfare (health, yield) and income cannot be achieved in dairy farms.
Oestrus (heat), which is normally observed year-round in cows, is short-term (average 18 hours) and ovulation (ovum-release) occurs after oestrus. Therefore, oestrus cannot be detected (suboestrus) in approximately 50% of cows, especially in large enterprises. In addition, while 50% conception related to artificial insemination (AI) is obtained all over the world, this rate may decrease down to 25% as a result of insufficient management and feeding, especially in large enterprises with high milk yield. Moreover, fertility (calf yield) decreases by about 2% with every 5 litres of milk increase per cow. On the other hand, when the same breeding male (bull line) is used for a long time, abnormalities or other yield losses (abortus) due to inbreeding within the herd may be inevitable. Even due to long-term inadequate management and feeding, the reproductive process may be stopped completely (anoestrus) along with a decrease in milk yield.
In our country, cattle breeding is mostly performed by low education-level breeders in enterprises with insufficient shelter and feeding conditions, by the low level of forage (straw, dry grass) and insufficient silage and/or concentrated feedstuff. In the East, small-scale (semi-primitive) enterprises, where mostly low-yielding indigenous/hybrid breeds preferred are dealing with degraded animal health rather than the yield (milk, calf). In the West, in medium-/large-sized enterprises, the minimum animal welfare level (normal lactation and annual calf yield) that can meet the demand for high milk (and calf) yields is not met. Undoubtedly, ensuring animal welfare and productivity is possible, along with the ideal level of management-feeding, through adequate and regular medical (Veterinary) services and breeding bull (AI with frozen semen).
Therefore, in order to overcome the economic difficulties in the dairy sector, modern animal husbandry requires solutions to; individual (insufficient professional knowledge, awareness, experience as well as team approach), animal (reproductive problems, low productivity), nutritional (insufficient or one-way feeding) and managerial (traditional approach) problems. In the near future, as the first step in the effective struggle against traditional animal health and husbandry culture in the field, modern education (mainly for vet surgeons, vet students, caretakers and breeders), surveillance, survey and publication studies should be focused on.
... TLR are a family of conserved trans-membrane protein family receptors that play a role in the recognition of preserved molecular motifs. In general, the structure of TLRs consists of the Nterminal and C-terminal domains domain, leucine-rich repeats (LRRs) and the highly conserved cytoplasmic Toll / IL-1 receptor (TIR) domain (Chen et al., 2013;Wu et al., 2018). Leucine-rich repeats (LRRs) support specific interactions between conserved membrane proteins (MAMP) and the TLR family. ...
ATATÜRK (1881-1938), a military genius and great reformist, has founded (1923) the new state of the Republic of TURKEY after World War I (1914-1918), especially via the Çanakkale Victory (1915), followed by the War of Independence (1919-1923). Over the 15 years since being elected as the first President, he has led major reforms in Anatolia (a geography with the cradle of civilizations), which previously lost millions (18 million dead) of its war-worn citizens (12 million alive), left uneducated (literacy rate: 10% in 1923; 97% in 2019) and unqualified (only 13% unemployed now, 2019). However, it was impossible, with military heroism only, to achieve the ultimate national goal of ‘contemporary civilizations’ level (1919), as indicated by ATATÜRK, the visionary leader. So, it was a national imperative that all the other sectors contribute massively to the spirit of the campaign in all fields of life (society and culture) as well as economy and industry (including marine, agriculture and animal production (husbandry and breeding)) for ultimate human well-being and animal welfare both.
In the Republican era (1923 onwards), the livestock policies included mainly; i) Updating the Ottoman Legislation (including the establishments of Veterinary education facilities in İstanbul and Ankara; now 32 Veterinary and 45 Agricultural Faculties and 202 Universities available), ii) Animal Health Protection (vaccines) and Disease Struggle (40% animal deaths by outbreaks declined to a minimum in 20 years, from 1919 to 1939), and iii) Livestock Breeding (mainly in Karacabey-Bursa and Lalahan-Ankara) and Production (nearly ‘three-fold’ increase, from 17 million in 1923 to 50 million by 1938; while 70 million today). Indeed, animal husbandry allowed mainly the basic needs for food (animal protein) and transport (in the battlefield/on the farm). Animal breeding (initially AI-artificial insemination, recently ET-embryo transfer and cloning) was not only increased the yield (meat, milk, egg, wool), but also allowed efficient struggle against infectious diseases seen (Brucellosis, Tuberculosis, Bovine Plague, FMD). To this end, Izmir Economic Congress (17 Feb.-4 March 1923) has brought the major initiative reforms in many economic sectors (banking, stock market, coal mining, railways, cooperatives, agricultural training), animal breeding (first AI in horse and sheep, 1926) and husbandry (in cattle, horse, buffalo, sheep, goat, gazelle, dog, cat, hen, goose, fish, honeybee) in many cities (Bursa, Ankara, Konya, Afyonkarahisar, Şanlıurfa, Kars, Ardahan, Ordu, Sivas, Denizli, Muğla).
During the years of war and the Republican era, cattle were used for food and transport (mostly indigenous and cross-bred). However, horses (stud farms in Bursa, Eskişehir, Malatya) were kept for riding (Arabian and English thoroughbred) and transport (indigenous), while sheep and goats (mostly indigenous) were used for food (indigenous) and wool/mohair (Merino, Angora). In animal breeding history, the first AI trials (dog) were started in the 1780s by L. Spallanzani (Italy), while bull semen freezing firstly performed by R. Foote (USA, 1936). In the early 1900s, Russia and Turkey were the first two countries adopting the cattle breeding (mainly Brown Swiss, Simmental, Holstein, and Jersey) (Lalahan, 1957). In our country, the breeding trials in sheep (Merino with thin wool) and cattle were in a partial rise, especially in the Marmara region, in the late 1920s. But World Economic Crisis 1929 (originated in the USA, spread to UK and Germany) and World War II (1939-1945) have led to local/global epidemics and recessions (nearly 50% weakening). So, breeding (AI) trials remained very low until the late 1950s. As with developed countries, pioneering breeding activities in Turkey have then gained momentum again due to increasing local/global welfare since the 1960s onwards (2 million dose bull sperm produced, 3 million AI performed, and 9 million female cattle present; in 2018). In our country, the AI was preferred for dairy (Holstein) breeding especially in the West (Thrace and the Aegean), while Brown-Swiss (combined) breed was used mostly in the East. Surely, the AI practices in cows have long been very common (nearly 75% AI, with success) in America (Holstein) and Europe (Holstein, Brown-Swiss, Simmental).
Clearly, sustainable breeding/production (with optimum feeding/care) was ensured in the livestock and the strategies followed by the State authorities were successful in the ATATÜRK and Republican era (broadly between 1920-2020). Surely, the efficient vaccines and recent technologies (USG, ET, cloning, transgenics/genomics, gene banking, special production) are also essential to keep up-to-date.
... TLR are a family of conserved trans-membrane protein family receptors that play a role in the recognition of preserved molecular motifs. In general, the structure of TLRs consists of the Nterminal and C-terminal domains domain, leucine-rich repeats (LRRs) and the highly conserved cytoplasmic Toll / IL-1 receptor (TIR) domain (Chen et al., 2013;Wu et al., 2018). Leucine-rich repeats (LRRs) support specific interactions between conserved membrane proteins (MAMP) and the TLR family. ...
Abstract
Poultry, which is an important part of human nutrition, have been affected by avian influenza virus, that it affected avian health and causes worrying economic losses, has different variants (H5N1, H5N2, H1N1, H7N7, H7N1 H3N8 and H7N3). Highly pathogenic avian influenza (HPAI) bird flu, which is highly pathogenic in chickens, negatively affects human health due to its zoonotic feature besides poultry. TLR (Toll-like receptors), is one of the receptors involved in the natural immune system that acts as the first line of defense against many invading pathogens in the channel infection process. As a result of genome analysis, there are ten TLR (toll-like receptors) in chickens and five of them are determined to be ortholog with TLR2a, 2b, 3,4,5 and 7. Chicken TLR21 has been found in fish and reptiles, TLR15 reported phylogenetically specific to the TLR2 family and poultry species. It has been reported that while TLR2 is preserved in mammal and poultry species, the other TLR2 family member occurs spontaneously. Chicken TLR2 shows the same dimerization feature as TLR1a and 1b. TLR9 is not found in the chicken genome, while TLR21 is found in the mammalian genome. The aim of this review is to discuss the cellular role of TLRs that play a role in the antiviral response mechanism of chicken cells in the case of virus-borne infections.
Keywords: Avian flu, TLR (Toll-like receptors), Infection, Antiviral response
... Therefore, the diversity of the undefined region suggested the TLR9 activities might result in considerable intrinsic variation among different fish species [48]. Interestingly, the undefined regions are have not been identified in fish TLR21 proteins like they have been in the homologous chicken TLR21 [66]. Further, TLR21 ectodomain regions, LRR14 and LRR15, are highly conserved, which suggests the biological function of TLR21s may be similar in different fish species [48]. ...
Studies of DNA vaccines have shown that understanding the mechanism of DNA vaccine-mediated action is the key for vaccine development. Current knowledge has shown the presence of antigen presenting cells (APCs) involving in B and T cells at the muscle injection site and the upregulation of type I interferon (IFN–I) that initiates antiviral response and benefits adaptive immunity in fish DNA vaccines. IFN-I may be triggered by expressed antigen such as the rhabdovirus G protein encoded DNA vaccine or by plasmid DNA itself through cytosolic DNA sensing. The investigating of Toll-like receptor 9, and 21 are the CpG-motif sensors in many fish species, and the cytosolic DNA receptors DDX41 and downstream STING signaling revealed the mechanisms for IFN-I production. This review article describes the recent finding of receptors for cytosolic DNA, the STING-TBK1-IRF signaling, and the possibility of turning these findings into strategies for the future development of DNA vaccines.
... In contrast, although TLR21 is functionally related to TLR9 in response to CpG-ODN stimulation, TLR21 is more phylogenetically related to members of the TLR11 subfamily and is an ortholog closer to the TLR13 subfamily (129,130). Analysis of chicken TLR21 revealed that it does not have an undefined region, as in TLR9. In addition, a study of TLR21 proteins from different species shows that these TLR21s are highly homologous (130). ...
... Analysis of chicken TLR21 revealed that it does not have an undefined region, as in TLR9. In addition, a study of TLR21 proteins from different species shows that these TLR21s are highly homologous (130). The same is true for teleost TLR21s. ...
Toll-like receptors (TLRs) are pattern-recognition receptors that detect a wide variety of microbial pathogens for the initiation of host defense immunological responses. Thirteen TLRs have been identified in mammals, and teleosts contain 22 mammalian or non-mammalian TLRs. Of these, TLR9 and TLR21 are the cytosine-phosphate-guanosine-oligodeoxynucleotides (CpG-ODNs) recognition TLRs in teleosts. TLR9 is a mammalian TLR expressed in teleost but not in the avian species. TLR21 is a non-mammalian TLR expressed in both teleost and the avian species. Synthetic CpG-ODNs are potent immunostimulants that are being studied for their application against tumors, allergies, and infectious diseases, and as a vaccine adjuvant in humans. The immunostimulatory effects of CpG-ODNs as vaccine adjuvants and their antimicrobial function in domestic animals and teleosts are also being investigated. Most of our current knowledge about the molecular basis for the immunostimulatory activity of CpG-ODNs comes from earlier studies of the interaction between CpG-ODN and TLR9. More recent studies indicate that in addition to TLR9, TLR21 is another receptor for CpG-ODN recognition in teleosts to initiate immune responses. Whether these two receptors have differential functions in mediating the immunostimulatory activity of CpG-ODN in teleost has not been well-studied. Nevertheless, the existence of two recognition TLRs suggests that the molecular basis for the immunostimulatory activity of CpG-ODN in teleosts is different and more complex than in mammals. This article reviews the current knowledge of TLR9 and TLR21 activation by CpG-ODNs. The key points that need to be considered for CpG-ODNs as immunostimulants with maximum effectiveness in activation of immune responses in teleosts are discussed. This includes the structure/activity relationship of CpG-ODN activities for TLR9 and TLR21, the structure/functional relationship of these two TLRs, and differential expression levels and tissue distributions for these two TLRs.
Background/aim:
Toll-like receptors (TLRs) are pivotal biomolecules in the immune system. Today, we are all aware of the importance of TLRs in bridging innate and adaptive immune system to each other. The TLRs are activated through binding to damage/danger-associated molecular patterns (DAMPs), microbial/microbe-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), and xenobiotic-associated molecular patterns (XAMPs). The immunogenetic molecules of TLRs have their own functions, structures, coreceptors, and ligands which make them unique. These properties of TLRs give us an opportunity to find out how we can employ this knowledge for ligand-drug discovery strategies to control TLRs functions and contribution, signaling pathways, and indirect activities. Hence, the authors of this paper have a deep observation on the molecular and structural biology of human TLRs (hTLRs).
Methods and materials:
To prepare this paper and fulfill our goals, different search engines (e.g., GOOGLE SCHOLAR), Databases (e.g., MEDLINE), and websites (e.g., SCOPUS) were recruited to search and find effective papers and investigations. To reach this purpose, we tried with papers published in the English language with no limitation in time. The iCite bibliometrics was exploited to check the quality of the collected publications.
Results:
Each TLR molecule has its own molecular and structural biology, coreceptor(s), and abilities which make them unique or a complementary portion of the others. These immunogenetic molecules have remarkable roles and are much more important in different sections of immune and nonimmune systems rather than that we understand to date.
Conclusion:
TLRs are suitable targets for ligand-drug discovery strategies to establish new therapeutics in the fields of infectious and autoimmune diseases, cancers, and other inflammatory diseases and disorders.
Protein–protein and protein–DNA/RNA interactions are involved in many cellular processes. Therefore, determining their complex structures at the atomic level is valuable to gain insights into these interactions. Because of the technical difficulties and high cost in experimental methods, computational approaches like molecular docking have been developed to predict the structures of macromolecular complexes in the last decades. To automatically integrate the available binding information from the PDB, we have developed HDOCK, a protein–protein/nucleic acid docking web server by combining template-based and free docking. In this chapter, we first briefly introduce our HDOCK server and then give a step-by-step description of docking bovine chymotrypsinogen A against its inhibitor (PDB ID: 1CGI). Two case studies of realistic examples are also discussed. The HDOCK server is freely available at http://hdock.phys.hust.edu.cn/.
