Myosin's powerstroke transitions define atomic scale movement of cardiac thin filament tropomyosin.

Dynamic interactions between the myosin motor head on thick filaments and the actin molecular track on thin filaments drive the myosin-crossbridge cycle that powers muscle contraction. The process is initiated by Ca2+ and the opening of troponin-tropomyosin-blocked myosin-binding sites on actin. The ensuing recruitment of myosin heads and their transformation from pre-powerstroke to post-powerstroke conformation on actin produce the force required for contraction. Cryo-EM-based atomic models confirm that during this process, tropomyosin occupies three different average positions on actin. Tropomyosin pivoting on actin away from a TnI-imposed myosin-blocking position accounts for part of the Ca2+ activation observed. However, the structure of tropomyosin on thin filaments that follows pre-powerstroke myosin binding and its translocation during myosin's pre-powerstroke to post-powerstroke transition remains unresolved. Here, we approach this transition computationally in silico. We used the myosin helix-loop-helix motif as an anchor to dock models of pre-powerstroke cardiac myosin to the cleft between neighboring actin subunits along cardiac thin filaments. We then performed targeted molecular dynamics simulations of the transition between pre- and post-powerstroke conformations on actin in the presence of cardiac troponin-tropomyosin. These simulations show Arg 369 and Glu 370 on the tip of myosin Loop-4 encountering identically charged residues on tropomyosin. The charge repulsion between residues causes tropomyosin translocation across actin, thus accounting for the final regulatory step in the activation of the thin filament, and, in turn, facilitating myosin movement along the filament. We suggest that during muscle activity, myosin-induced tropomyosin movement is likely to result in unencumbered myosin head interactions on actin at low-energy cost.

Identification of the pan-allergen tropomyosin from the common bed bug (Cimex lectularius).

Tropomyosin is a muscle contraction protein documented across all animal life. Despite its ubiquity, its unique structure in invertebrates leads to allergic responses in humans that vertebrate tropomyosin does not. High degrees of homology can explain cross-reactivity between tropomyosin derived from distantly-related arthropod species and establishes tropomyosin as a panallergen. Given this cross-reactivity and that they are commonly found in high numbers indoors, research on the potential of the common bed bug (Cimex lectularius L.) to contribute tropomyosin to the indoor environment is needed. Therefore, we investigated tropomyosin homology between bed bugs and known tropomyosin allergens from other taxa, tropomyosin in bed bug bodies, feces, and exuviae (cast skins), tropomyosin persistence over time, and impacts of common bed bug treatment strategies on detectable tropomyosin. Tropomyosin was detected in mechanically fractured bed bug cadavers and was detectable in bed bugs cadavers aged for 18 months. Additionally, a survey of pest management professionals showed dead bed bugs are not cleaned up following treatment. As such, dead bed bugs could act as tropomyosin reservoirs following bed bug treatment and exposure to tropomyosin from bed bugs could sensitize individuals and lead to increased responses to other arthropod tropomyosin.

Differential expression of TRKB tyrosine kinase in the two histological types of parotid salivary duct carcinoma with cancer aggressiveness.

Parotid salivary duct carcinoma (SDC) is a rare and aggressive parotid gland carcinoma (PGC). SDC has two origins: de novo and ex pleomorphic adenoma (SDC ex PA); however, because of its rarity, the clinical and molecular features of the two types of SDC are not sufficiently understood. Here, we studied the differences in their clinicopathological and molecular features using clinical specimens while comparing them to those of adenoid cystic carcinoma (AdCC), an intermediate-grade PGC. Clinicopathological analysis of tissues from patients with PGC revealed significant associations between histological types and malignant phenotypes, including nodal metastasis, recurrence, vascular invasion, and neural invasion, and revealed more malignant phenotypes of de novo SDC than of SDC ex PA. The de novo SDC showed a significantly higher frequency of intra-neural invasion (intra-NI) and vascular invasion than AdCC and SDC ex PA. PGCs with high intra-NI were significantly correlated with malignant phenotypes and survival rates. Recently, we observed the overexpression of tropomyosin receptor kinase B (TRKB), a receptor tyrosine kinase, in PGC cells. Here, immunohistochemical and clinicopathological analyses showed that TRKB was highly expressed in SDC cells, particularly de novo SDC cells, and was significantly associated with poor survival and highly malignant phenotypes, including intra-NI and vascular invasion. Collectively, these data show that TRKB expression is significantly elevated in PGC, particularly in de novo SDC, and can be one of the biomarkers of their aggressiveness.

Colorimetric and surface-enhanced Raman scattering dual-mode lateral flow immunosensor using phage-displayed shark nanobody for the detection of crustacean allergen tropomyosin.

Tropomyosin (TM) is the primary allergenic protein responsible for crustacean food allergies, and thus sensitive and rapid methods are required for the screening of crustacean TM in food. In this study, using the phage-displayed shark nanobody (PSN) as a multifunctional biomaterial, we developed a colorimetric and surface-enhanced Raman scattering dual-mode lateral flow immunosensor (CM/SERS-LFI) for competitive detection of crustacean TM. The SERS tag AuMBA@AgNPs with the Raman signal molecule 4-mercaptobenzoic acid (4-MBA) was prepared and immobilized on the PSN to construct the immunoprobe AuMBA@Ag-PSN. The probe can identify free TM that competes with TM on the T-line, and the optimized CM/SERS-LFI enables quantitative analysis of TM using the probe with a limit of detection (LOD) of 0.0026 µg/mL (SERS mode) and 0.0057 µg/mL (colorimetric mode), respectively. Additionally, it can implement a qualitative analysis by the naked eye with a visual LOD of 0.01 µg/mL. The CM/SERS-LFI exhibited excellent performance in the tests of selectivity, accuracy, precision, and stability. Moreover, the method's effectiveness in the analysis of real samples was confirmed by a commercial ELISA kit. Therefore, the developed CM/SERS-LFI was demonstrated to be a powerful and reliable tool for the rapid and sensitive detection of crustacean TM in food.

Troponin Structural Dynamics in the Native Cardiac Thin Filament Revealed by Cryo Electron Microscopy.

Cardiac muscle contraction occurs due to repetitive interactions between myosin thick and actin thin filaments (TF) regulated by Ca2+ levels, active cross-bridges, and cardiac myosin-binding protein C (cMyBP-C). The cardiac TF (cTF) has two nonequivalent strands, each comprised of actin, tropomyosin (Tm), and troponin (Tn). Tn shifts Tm away from myosin-binding sites on actin at elevated Ca2+ levels to allow formation of force-producing actomyosin cross-bridges. The Tn complex is comprised of three distinct polypeptides - Ca2+-binding TnC, inhibitory TnI, and Tm-binding TnT. The molecular mechanism of their collective action is unresolved due to lack of comprehensive structural information on Tn region of cTF. C1 domain of cMyBP-C activates cTF in the absence of Ca2+ to the same extent as rigor myosin. Here we used cryo-EM of native cTFs to show that cTF Tn core adopts multiple structural conformations at high and low Ca2+ levels and that the two strands are structurally distinct. At high Ca2+ levels, cTF is not entirely activated by Ca2+ but exists in either partially or fully activated state. Complete dissociation of TnI C-terminus is required for full activation. In presence of cMyBP-C C1 domain, Tn core adopts a fully activated conformation, even in absence of Ca2+. Our data provide a structural description for the requirement of myosin to fully activate cTFs and explain increased affinity of TnC to Ca2+ in presence of active cross-bridges. We suggest that allosteric coupling between Tn subunits and Tm is required to control actomyosin interactions.

Reducing the allergenicity of tropomyosin in shrimp by covalent conjugation with quercetin and chlorogenic acid.

The study aimed to assay the allergenicity of shrimp tropomyosin (TM) following covalent conjugation with quercetin (QR) and chlorogenic acid (CA). The structure of the TM-polyphenol covalent conjugates was examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), fluorescence, differential scanning calorimetry (DSC), and Fourier Transform infrared spectroscopy (FTIR). Potential allergenicity was evaluated using in vitro and in vivo methods. The results showed that QR and CA induced structural changes in TM through aggregation. RBL-2H3 cell results showed that TM-QR and TM-CA covalent conjugates reduced the release of ß-hexosaminidase and histamine, respectively. In the mice model, TM-QR and TM-CA covalent conjugates reduced the level of IgE, IgG, IgG1, histamine, and mMCP-1 in sera. Furthermore, the allergenicity was reduced by suppressing Th2-related cytokines (IL-4, IL-5, IL-13) and promoting Th1-related cytokines (IFN-γ). These research findings demonstrate that the covalent binding of TM with QR and CA, modifies the allergenic epitopes of shrimp TM, thereby reducing its potential allergenicity. This approach holds practical applications in the production of low-allergenicity food within the food industry.

Paramyosin from field snail (Bellamya quadrata): Structural characteristics and its contribution to enhanced the gel properties of myofibrillar protein.

To assess the blending effect of field snails with grass carp muscle, the effects of paramyosin (PM) and actomyosin (AM) with different mixture ratios on the gel properties of the binary blend system were investigated in our work. The purified PM from field snail muscle was about 95 kDa on SDS-PAGE. Its main secondary structure was α-helix, which reached to 97.97 %. When the amount of PM increased in the binary blend system, their rheological indices and gel strength were improved. The water holding capacity (WHC) increased to 86.30 % at a mixture ratio of 2:8. However, the WHC and the area of immobile water (P22) dramatically decreased, and the area of free water (P23) increased when the mixture ratio exceeded 4:6. The low level of PM in binary blend system promoted the formation of a homogenous and dense gel network through non-covalent interactions as observed results of SEM and FTIR. When there were redundant PM molecules, the development of heterostructure via hydrophobic interaction of tail-tail contributed to the reduced gel properties of the binary blend system. These findings provided new insight into the binary blend system of PM and AM with different ratios to change the gel properties of myofibrillar protein.

Allergic Reaction to a Commercially Available Insect Snack Caused by House Cricket (Acheta domesticus) Tropomyosin.

SCOPE: Edible insects contain allergens with potential cross-reactivity to other invertebrates. Here, this study examines IgE-reactive proteins in a house cricket snack (Acheta domesticus) leading to an allergic reaction in a 27-year old man followed by a similar reaction days later after eating shrimps. METHODS AND RESULTS: Prick to prick tests verify the IgE-mediated allergy to crickets and skin prick testing confirms a type I sensitization to house dust mite without any clinical relevance for the patient, and to shrimp extracts, but is negative for several other foods. Serological testing reveals a sensitization to shrimps, shrimp tropomyosin, and house dust mite tropomyosin. IgE-immunodetection shows that the cricket allergic patient is sensitized to two proteins of 45 and >97 kDa using aqueous control cricket extract, but to only one protein at around 45 kDa when using the causative, seasoned insect snack extract. Mass spectrometry data and IgE-inhibition experiments clearly identify this protein belonging to the tropomyosin allergen family. CONCLUSION: This case report suggests that cricket tropomyosin may be an elicitor of allergic reactions even in previously not allergic patients, although it cannot be excluded the patient reacted additionally to other ingredients of the snack.

Lactobacillus brevis-Fermented Gamma-Aminobutyric Acid Ameliorates Depression- and Anxiety-Like Behaviors by Activating the Brain-Derived Neurotrophic Factor-Tropomyosin Receptor Kinase B Signaling Pathway in BALB/C Mice.

This study investigated the effects of Lactobacillus brevis-fermented gamma-aminobutyric acid (LB-GABA) on depressive and anxiety-like behaviors with the underlying molecular mechanism in a chronic stress model of BALB/c mice. LB-GABA attenuates both neuronal cell death and the increase of monoamine oxidase activity induced by hydrogen peroxide. Behavioral tests revealed that GABA significantly increased sucrose preference and reduced immobility time in both tail suspension and forced swimming tests. LB-GABA increased exploration of the open arms in the elevated plus maze and restored activity in the open field. Moreover, LB-GABA lowered stress hormone and inflammatory mediator levels. Mechanistically, LB-GABA increased protein levels of BDNF and TrkB, activating downstream targets (AKT, ERK, and CREB), crucial for neuronal survival and plasticity. Furthermore, LB-GABA protected hippocampal neurons from stress-induced cell death and increased serotonin and dopamine levels. Overall, LB-GABA has the potential to alleviate stress-induced depression and anxiety-like symptoms and neuroinflammation by activating the BDNF-TrkB signaling pathway.

Chlorogenic acid alleviates crayfish allergy by altering the structure of crayfish tropomyosin and upregulating TLR8.

Studies have shown that high hydrostatic pressure (HHP) processing and chlorogenic acid (CA) treatment can effectively reduce food allergenicity. We hypothesize that these novel processing techniques can help tackle crayfish allergy and examined the impact and mechanism of HHP (300 MPa, 15 min) and CA (CA:tropomyosin = 1:4000, 15 min) on the allergenicity of crayfish tropomyosin. Our results revealed that CA, rather than HHP, effectively reduced tropomyosin's allergenicity, as evident in the alleviation of allergic symptoms in a food allergy mouse model. Spectroscopy and molecular docking analyses demonstrated that CA could reduce the allergenicity of tropomyosin by covalent or non-covalent binding, altering its secondary structure (2.1 % decrease in α-helix; 1.9 % increase in ß-fold) and masking tropomyosin's linear epitopes. Moreover, CA-treated tropomyosin potentially induced milder allergic reactions by up-regulating TLR8. While our results supported the efficacy of CA in alleviating crayfish allergy, further exploration is needed to determine clinical effectiveness.

Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors.

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRKWT, TRKG595R and TRKG667C with IC50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC50 = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

Tropomyosin 1-I/C coordinates kinesin-1 and dynein motors during oskar mRNA transport.

Dynein and kinesin motors mediate long-range intracellular transport, translocating towards microtubule minus and plus ends, respectively. Cargoes often undergo bidirectional transport by binding to both motors simultaneously. However, it is not known how motor activities are coordinated in such circumstances. In the Drosophila female germline, sequential activities of the dynein-dynactin-BicD-Egalitarian (DDBE) complex and of kinesin-1 deliver oskar messenger RNA from nurse cells to the oocyte, and within the oocyte to the posterior pole. We show through in vitro reconstitution that Tm1-I/C, a tropomyosin-1 isoform, links kinesin-1 in a strongly inhibited state to DDBE-associated oskar mRNA. Nuclear magnetic resonance spectroscopy, small-angle X-ray scattering and structural modeling indicate that Tm1-I/C suppresses kinesin-1 activity by stabilizing its autoinhibited conformation, thus preventing competition with dynein until kinesin-1 is activated in the oocyte. Our work reveals a new strategy for ensuring sequential activity of microtubule motors.

Lateral Flow Immunochromatographic Assay for Competitive Detection of Crustacean Allergen Tropomyosin Using Phage-Displayed Shark Single-Domain Antibody.

The common food allergy crustacean tropomyosin (TM) poses a significant food safety challenge, which requires rapid and sensitive methods for screening TM in food. Herein, the variable new antigen receptor (VNAR) single-domain antibodies specific for the crustacean TM were isolated from a naïve phage-displayed shark VNAR library. Subsequently, a lateral flow immunochromatographic assay (LFIA) based on the gold nanoparticle-labeled phage-displayed shark VNAR (AuNPs@PSV) probe was developed for the detection of TM in food. The AuNPs@PSV-LFIA took 15 min for one test and had a visual limit of detection (vLOD) of 0.1 µg/mL and an instrumental LOD of 0.02 µg/mL. Good selectivity, accuracy, precision, and stability were confirmed for the AuNPs@PSV-LFIA. Moreover, the test results of 21 commercially available food products consisted of the allergen labels and were validated by a commercial ELISA kit. Therefore, this work demonstrated the great potential of VNAR for detecting TM in food by LFIA.

Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection.

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.

Myopathy-causing mutation R91P in the TPM3 gene drastically impairs structural and functional properties of slow skeletal muscle tropomyosin γß-heterodimer.

Tropomyosin (Tpm) is a regulatory actin-binding protein involved in Ca2+ activation of contraction of striated muscle. In human slow skeletal muscles, two distinct Tpm isoforms, γ and ß, are present. They interact to form three types of dimeric Tpm molecules: γγ-homodimers, γß-heterodimers, or ßß-homodimers, and a majority of the molecules are present as γß-Tpm heterodimers. Point mutation R91P within the TPM3 gene encoding γ-Tpm is linked to the condition known as congenital fiber-type disproportion (CFTD), which is characterized by severe muscle weakness. Here, we investigated the influence of the R91P mutation in the γ-chain on the properties of the γß-Tpm heterodimer. We found that the R91P mutation impairs the functional properties of γß-Tpm heterodimer more severely than those of earlier studied γγ-Tpm homodimer carrying this mutation in both γ-chains. Since a significant part of Tpm molecules in slow skeletal muscle is present as γß-heterodimers, our results explain why this mutation leads to muscle weakness in CFTD.

Variants in tropomyosins TPM2 and TPM3 causing muscle hypertonia.

Patients with myopathies caused by pathogenic variants in tropomyosin genes TPM2 and TPM3 usually have muscle hypotonia and weakness, their muscle biopsies often showing fibre size disproportion and nemaline bodies. Here, we describe a series of patients with hypercontractile molecular phenotypes, high muscle tone, and mostly non-specific myopathic biopsy findings without nemaline bodies. Three of the patients had trismus, whilst in one patient, the distal joints of her fingers flexed on extension of the wrists. In one biopsy from a patient with a rare TPM3 pathogenic variant, cores and minicores were observed, an unusual finding in TPM3-caused myopathy. The variants alter conserved contact sites between tropomyosin and actin.

Glutamate 139 of tropomyosin is critical for cardiac thin filament blocked-state stabilization.

The cardiac thin filament proteins troponin and tropomyosin control actomyosin formation and thus cardiac contractility. Calcium binding to troponin changes tropomyosin position along the thin filament, allowing myosin head binding to actin required for heart muscle contraction. The thin filament regulatory proteins are hot spots for genetic mutations causing heart muscle dysfunction. While much of the thin filament structure has been characterized, critical regions of troponin and tropomyosin involved in triggering conformational changes remain unresolved. A poorly resolved region, helix-4 (H4) of troponin I, is thought to stabilize tropomyosin in a position on actin that blocks actomyosin interactions at low calcium concentrations during muscle relaxation. We have proposed that contact between glutamate 139 on tropomyosin and positively charged residues on H4 leads to blocking-state stabilization. In this study, we attempted to disrupt these interactions by replacing E139 with lysine (E139K) to define the importance of this residue in thin filament regulation. Comparison of mutant and wild-type tropomyosin was carried out using in-vitro motility assays, actin co-sedimentation, and molecular dynamics simulations to determine perturbations in troponin-tropomyosin function caused by the tropomyosin mutation. Motility assays revealed that mutant thin filaments moved at higher velocity at low calcium with increased calcium sensitivity demonstrating that tropomyosin residue 139 is vital for proper tropomyosin-mediated inhibition during relaxation. Similarly, molecular dynamic simulations revealed a mutation-induced decrease in interaction energy between tropomyosin-E139K and troponin I (R170 and K174). These results suggest that salt-bridge stabilization of tropomyosin position by troponin IH4 is essential to prevent actomyosin interactions during cardiac muscle relaxation.

Auricular Vagal Nerve Stimulation Inhibited Central Nerve Growth Factor/Tropomyosin Receptor Kinase A/Phospholipase C-Gamma Signaling Pathway in Functional Dyspepsia Model Rats With Gastric Hypersensitivity.

OBJECTIVE: Functional dyspepsia (FD), which has a complicated pathophysiologic process, is a common functional gastrointestinal disease. Gastric hypersensitivity is the key pathophysiological factor in patients with FD with chronic visceral pain. Auricular vagal nerve stimulation (AVNS) has the therapeutic effect of reducing gastric hypersensitivity by regulating the activity of the vagus nerve. However, the potential molecular mechanism is still unclear. Therefore, we investigated the effects of AVNS on the brain-gut axis through the central nerve growth factor (NGF)/ tropomyosin receptor kinase A (TrkA)/phospholipase C-gamma (PLC-γ) signaling pathway in FD model rats with gastric hypersensitivity. MATERIALS AND METHODS: We established the FD model rats with gastric hypersensitivity by means of colon administration of trinitrobenzenesulfonic acid on ten-day-old rat pups, whereas the control rats were given normal saline. AVNS, sham AVNS, K252a (an inhibitor of TrkA, intraperitoneally), and K252a + AVNS were performed on eight-week-old model rats for five consecutive days. The therapeutic effect of AVNS on gastric hypersensitivity was determined by the measurement of abdominal withdrawal reflex response to gastric distention. NGF in gastric fundus and NGF, TrkA, PLC-γ, and transient receptor potential vanilloid 1 (TRPV1) in the nucleus tractus solitaries (NTS) were detected separately by polymerase chain reaction, Western blot, and immunofluorescence tests. RESULTS: It was found that a high level of NGF in gastric fundus and an upregulation of the NGF/TrkA/PLC-γ signaling pathway in NTS were manifested in model rats. Meanwhile, both AVNS treatment and the administration of K252a not only decreased NGF messenger ribonucleic acid (mRNA) and protein expressions in gastric fundus but also reduced the mRNA expressions of NGF, TrkA, PLC-γ, and TRPV1 and inhibited the protein levels and hyperactive phosphorylation of TrkA/PLC-γ in NTS. In addition, the expressions of NGF and TrkA proteins in NTS were decreased significantly after the immunofluorescence assay. The K252a + AVNS treatment exerted a more sensitive effect on regulating the molecular expressions of the signal pathway than did the K252a treatment. CONCLUSION: AVNS can regulate the brain-gut axis effectively through the central NGF/TrkA/PLC-γ signaling pathway in the NTS, which suggests a potential molecular mechanism of AVNS in ameliorating visceral hypersensitivity in FD model rats.

Exploration of digestion-resistant immunodominant epitopes in shrimp (Penaeus vannamei) allergens.

The digestion products of Penaeus vannamei still had sensitizing and eliciting capacity; however, the underlying mechanism has not been identified. This study analyzed the structural changes of shrimp proteins during digestion, predicted the linearmimotopepeptides and first validated the allergenicity of immunodominantepitopes with binding ability. The results showed that the shrimp proteins were gradually degraded into small peptides during digestion, which might lead to the destruction of linear epitopes. However, these peptides carried IgE epitopes that still trigger allergic reactions. Eighteen digestion-resistant epitopes were predicted by multiple immunoinformatics tools and digestomics. Five epitopes contained more critical amino acids and had strong molecular docking (P1: DSGVGIYAPDAEA, P2: EGELKGTYYPLTGM, P3: GRQGDPHGKFDLPPGV, P4: IFAWPHKDNNGIE, P5: KSTESSVTVPDVPSIHD), and these epitopes were identified as novel IgE binding immunodominantepitopes in Penaeus vannamei. These findings provide novel insight into allergenic epitopes, which might serve as key targets for reducing the allergenicity in shrimp.

Discovery of Tropomyosin Receptor Kinase Inhibitors as New Generation Anticancer Agents: A Review.

BACKGROUND: The tropomyosin receptor kinases (TRKs) are crucial for many cellular functions, such as growth, motility, differentiation, and metabolism. Abnormal TRK signalling contributes to a variety of human disorders, most evidently cancer. Comprehensive genomic studies have found numerous changes in the genes that code for TRKs like MET, HER2/ErbB2, and EGFR, among many others. Precision medicine resistance, relapse occurring because of the protein point mutations, and the existence of multiple molecular feedback loops are significant therapeutic hurdles to the long-term effectiveness of TRK inhibitors as general therapeutic agents for the treatment of cancer. OBJECTIVE: This review is carried out to highlight the role of tropomyosin receptor kinase in cancer and the function of TRK inhibitors in the intervention of cancer. METHODS: Literature research has been accomplished using Google Scholar and databases like ScienceDirect, WOS, PubMed, SciFinder, and Scopus. RESULTS: In this review, we provide an overview of the main molecular and functional properties of TRKs and their inhibitors. It also discusses how these advancements have affected the development and use of novel treatments for malignancies and other conditions caused by activated TRKs. Several therapeutic strategies, including the discovery and development of small-molecule TRK inhibitors belonging to various chemical classes and their activity, as well as selectivity towards the receptors, have been discussed in detail. CONCLUSION: This review will help the researchers gain a fundamental understanding of TRKs, how this protein family works, and the ways to create chemical moieties, such as TRK inhibitors, which can serve as tailored therapies for cancer.