A comprehensive in silico analysis of putative outer membrane and secretory hydrolases from the pathogenic Leptospira: Possible implications in pathogenesis.

Outer surface/membrane and virulent secretory proteins are primarily crucial for pathogenesis. Secreted and outer membrane hydrolases of many pathogens play an important role in attenuating the host immune system. Leptospira expresses many such proteins, and few have been characterized to display various roles, including host immune evasion.

Crystal structure of a variable region segment of Leptospira host-interacting outer surface protein, LigA, reveals the orientation of Ig-like domains.

Leptospiral immunoglobulin-like (Lig) protein family is a surface-exposed protein from the pathogenic Leptospira. The Lig protein family has been identified as an essential virulence factor of L. interrogan.

Biochemical characterization, substrate and stereoselectivity of an outer surface putative α/β hydrolase from the pathogenic Leptospira.

The genome of pathogenic leptospira encodes a plethora of outer surface and secretory proteins. The outer surface or secreted α/β hydrolases in a few pathogenic organisms are crucial virulent factors. They hydrolyze host immune factors and pathogen's immune-activating ligands, which help pathogens to evade the host's innate immunity.

Multiepitope-based vaccine design by exploring antigenic potential among leptospiral lipoproteins using comprehensive immunoinformatics and structure-based approaches.

Leptospirosis is a tropical and globally neglected zoonotic disease caused by pathogenic spirochetes, Leptospira. Although the disease has been studied for decades, a potent or effective vaccine is not available so far. Efforts are being made to design an efficient vaccine candidate using different approaches.

Characterization of novel nuclease and protease activities among Leptospiral immunoglobulin-like proteins.

Bacterial immunoglobulin-like (BIg) domain containing proteins play a variety of biological functions. Leptospiral Immunoglobulin-like (Lig) proteins are well-known virulence factors located on the surface of the pathogenic Leptospira that act during adhesion, invasion, and immune evasion. The Lig proteins have many roles and have been designated as multifaceted proteins.

Probing structural basis for enhanced binding of SARS-CoV-2 P.1 variant spike protein with the human ACE2 receptor.

The initial step of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the binding of receptor binding domain (RBD) of the spike protein to the angiotensin converting enzyme 2 (ACE2) receptor. Each successive wave of SARS-CoV-2 reports emergence of many new variants, which is associated with mutations in the RBD as well as other parts of the spike protein. These mutations are reported to have enhanced affinity towards the ACE2 receptor as well as are also crucial for the virus transmission.

Enzyme engineering improves catalytic efficiency and enantioselectivity of hydroxynitrile lyase for promiscuous retro-nitroaldolase activity.

Protein engineering to improve promiscuous catalytic activity is important for biocatalytic application of enzymes in green synthesis. We uncovered the significance of binding site residues in Arabidopsis thaliana hydroxynitrile lyase (AtHNL) for promiscuous retro-nitroaldolase activity. Engineering of AtHNL has improved enantioselective retro-nitroaldolase activity, a synthetically important biotransformation, for the production of enantiopure β-nitroalcohols having absolute configuration opposite to that of the stereopreference of the HNL.

Immunoinformatics-Based Designing of a Multi-Epitope Chimeric Vaccine From Multi-Domain Outer Surface Antigens of .

Accurate information on antigenic epitopes within a multi-domain antigen would provide insights into vaccine design and immunotherapy. The multi-domain outer surface immunoglobulin-like (Lig) proteins LigA and LigB, consisting of 12-13 homologous bacterial Ig (Big)-like domains, are potential antigens of . Currently, no effective vaccine is available against pathogenic .

Phosphorylation of eukaryotic initiation factor eIFiso4E enhances the binding rates to VPg of turnip mosaic virus.

Binding of phosphorylated eIFiso4E with viral genome-linked protein (VPg) of turnip mosaic virus was examined by stopped-flow, fluorescence, circular dichroism (CD) spectroscopy, and molecular docking analysis. Phosphorylation of eIFiso4E increased (4-fold) the binding rates as compared to unphosphorylated eIFiso4E with VPg. Stopped-flow kinetic studies of phosphorylated eIFiso4E with VPg showed a concentration-independent conformational change.

Immunoinformatics analysis of antigenic epitopes and designing of a multi-epitope peptide vaccine from putative nitro-reductases of Mycobacterium tuberculosis DosR.

Mycobacterium tuberculosis (Mtb) resides in alveolar macrophages as a non-dividing and dormant state causing latent tuberculosis. Currently, no vaccine is available against the latent tuberculosis. Latent Mtb expresses ~48 genes under the control of DosR regulon.

Comparative protein structure network analysis on 3CL from SARS-CoV-1 and SARS-CoV-2.

The main protease M , 3CL is an important target from coronaviruses. In spite of having 96% sequence identity among M from SARS-CoV-1 and SARS-CoV-2; the inhibitors used to block the activity of SARS-CoV-1 M so far, were found to have differential inhibitory effect on M of SARS-CoV-2. The possible reason could be due to the difference of few amino acids among the peptidases.

Structure-based identification of natural compound inhibitor against thioredoxin reductase: insight from molecular docking and dynamics simulation.

Antioxidant systems of () play an important role in providing resistance in the hostile environment of mononuclear phagocytes. Thioredoxin system is a known antioxidant system that consists of three copies of thioredoxins (Trxs) and a single copy of thioredoxin reductase (TrxR). TrxR has been validated as an essential gene known to be involved in the reduction of peroxides, dinitrobenzenes and hydroperoxides, and is crucial in maintaining the survival of in macrophages.

Comparative screening of recombinant antigen thermostability for improved leptospirosis vaccine design.

Recombinant antigens exhibit targeted protectiveproperties and offer important opportunities in the development of therapeutic technologies. Biophysical and structural methods have become important tools for the rational design and engineering of improved antigen-based vaccines. Vaccines containing Leptospira immunoglobulin-like (Lig) protein-derived antigens are currently the most promising candidates for protective immunity against the globally prevalent bacterial pathogen, Leptospira interrogans; however, vaccine trials using these domains have produced inconsistent results.

Leptospira surface adhesin (Lsa21) induces Toll like receptor 2 and 4 mediated inflammatory responses in macrophages.

Leptospirosis is zoonotic and emerging infectious disease of global importance. Little is understood about Leptospira pathogenesis and host immune response. In the present work we have investigated how Leptospira modulates the host innate immune response mediated by Toll-like receptors (TLRs) via surface exposed proteins.

Interkingdom pharmacology of Angiotensin-I converting enzyme inhibitor phosphonates produced by actinomycetes.

The K-26 family of bacterial secondary metabolites are N-modified tripeptides terminated by an unusual phosphonate analog of tyrosine. These natural products, produced via three different actinomycetales, are potent inhibitors of human angiotensin-I converting enzyme (ACE). Herein we investigate the interkingdom pharmacology of the K-26 family by synthesizing these metabolites and assessing their potency as inhibitors of both the N-terminal and C-terminal domains of human ACE.

Molecular and thermodynamic mechanisms of the chloride-dependent human angiotensin-I-converting enzyme (ACE).

Somatic angiotensin-converting enzyme (sACE), a key regulator of blood pressure and electrolyte fluid homeostasis, cleaves the vasoactive angiotensin-I, bradykinin, and a number of other physiologically relevant peptides. sACE consists of two homologous and catalytically active N- and C-domains, which display marked differences in substrate specificities and chloride activation. A series of single substitution mutants were generated and evaluated under varying chloride concentrations using isothermal titration calorimetry.

Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin-I converting enzyme.

Human somatic angiotensin-I converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase and a central component of the renin angiotensin aldosterone system (RAAS). Its involvement in the modulation of physiological actions of peptide hormones has positioned ACE as an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the crystal structures of the two catalytic domains of human ACE (N- and C-) in complex with FI, the S enantiomer of the phosphinic ACE/ECE-1 (endothelin converting enzyme) dual inhibitor FII, to a resolution of 1.

Structural basis of peptide recognition by the angiotensin-1 converting enzyme homologue AnCE from Drosophila melanogaster.

Unlabelled: Human somatic angiotensin-1 converting enzyme (ACE) is a zinc-dependent exopeptidase, that catalyses the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a C-terminal dipeptide. It is the principal component of the renin-angiotensin-aldosterone system that regulates blood pressure. Hence it is an important therapeutic target for the treatment of hypertension and cardiovascular disorders.

Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril.

Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin-angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org.

Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide.

Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1).

Crystal structure of a phosphonotripeptide K-26 in complex with angiotensin converting enzyme homologue (AnCE) from Drosophila melanogaster.

Angiotensin-I converting enzyme (ACE, a zinc dependent dipeptidyl carboxypeptidase) is a major target of drugs due to its role in the modulation of blood pressure and cardiovascular disorders. Here we present a crystal structure of AnCE (an ACE homologue from Drosophila melanogaster with a single enzymatic domain) in complex with a natural product-phosphonotripeptide, K-26 at 1.96A resolution.

High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs.

Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities toward various substrates.

Mapping conformational transitions in cyclic AMP receptor protein: crystal structure and normal-mode analysis of Mycobacterium tuberculosis apo-cAMP receptor protein.

Cyclic AMP (cAMP) receptor protein, which acts as the sensor of cAMP levels in cells, is a well-studied transcription factor that is best known for allosteric changes effected by the binding of cAMP. Although genetic and biochemical data on the protein are available from several sources, structural information about the cAMP-free protein has been lacking. Therefore, the precise atomic events that take place upon binding of cAMP, leading to conformational changes in the protein and its activation to bind DNA, have been elusive.

Functional studies of multiple thioredoxins from Mycobacterium tuberculosis.

Cytoplasmic protein reduction via generalized thiol/disulfide exchange reactions and maintenance of cellular redox homeostasis is mediated by the thioredoxin superfamily of proteins. Here, we describe the characterization of the thioredoxin system from Mycobacterium tuberculosis, whose genome bears the potential to encode three putative thioredoxins from the open reading frames designated trxAMtb, trxBMtb, and trxCMtb. We show that all three thioredoxins, overproduced in Escherichia coli, are able to reduce insulin, a model substrate, in the presence of dithiothreitol.