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Nature Reviews. Cancer Feb 2018The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of... (Review)
Review
The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials. Novel approaches for targeting TP53 nonsense mutations are also underway. This Review discusses recent progress in pharmacological reactivation of mutant p53 and highlights problems and promises with these strategies.
Topics: Animals; Antineoplastic Agents; Cell Death; Humans; Mutant Proteins; Mutation; Neoplasms; Tumor Suppressor Protein p53
PubMed: 29242642
DOI: 10.1038/nrc.2017.109 -
Advances in Experimental Medicine and... 2016Identification of mutant proteins in biological samples is one of the emerging areas of proteogenomics. Despite the fact that only a limited number of studies have been... (Review)
Review
Identification of mutant proteins in biological samples is one of the emerging areas of proteogenomics. Despite the fact that only a limited number of studies have been published up to now, it has the potential to recognize novel disease biomarkers that have unique structure and desirably high specificity. Such properties would identify mutant proteoforms related to diseases as optimal drug targets useful for future therapeutic strategies. While mass spectrometry has demonstrated its outstanding analytical power in proteomics, the most frequently applied bottom-up strategy is not suitable for the detection of mutant proteins if only databases with consensus sequences are searched. It is likely that many unassigned tandem mass spectra of tryptic peptides originate from single amino acid variants (SAAVs). To address this problem, a couple of protein databases have been constructed that include canonical and SAAV sequences, allowing for the observation of mutant proteoforms in mass spectral data for the first time. Since the resulting large search space may compromise the probability of identifications, a novel concept was proposed that included identification as well as verification strategies. Together with transcriptome based approaches, targeted proteomics appears to be a suitable method for the verification of initial identifications in databases and can also provide quantitative insights to expression profiles, which often reflect disease progression. Important applications in the field of mutant proteoform identification have already highlighted novel biomarkers in large-scale investigations.
Topics: Amino Acid Sequence; Amino Acid Substitution; Databases, Protein; Humans; Mutant Proteins; Mutation; Peptide Fragments; Peptide Mapping; Polymorphism, Single Nucleotide; Proteogenomics; Proteolysis; Tandem Mass Spectrometry; Trypsin
PubMed: 27686807
DOI: 10.1007/978-3-319-42316-6_6 -
Emerging Topics in Life Sciences Sep 2020There are near-to-infinite combinations of possibilities for evolution to happen within nature, making it yet impossible to predict how it occurs. However, science is... (Review)
Review
There are near-to-infinite combinations of possibilities for evolution to happen within nature, making it yet impossible to predict how it occurs. However, science is now able to understand the mechanisms underpinning the evolution of biological systems and can use this knowledge to experimentally mimic nature. The fundamentals of evolution have been used in vitro to improve enzymes as suitable biocatalysts for applications in a process called 'Directed Evolution of Enzymes' (DEE). It replicates nature's evolutionary steps of introducing genetic variability into enzymes, selecting the fittest variants and transmitting the genetic information for the next generation. DEE has tailored biocatalysts for applications, expanding the repertoire of enzymatic activities, besides providing experimental evidences to support mechanistic hypotheses of molecular evolution and deepen our understanding about nature. In this mini review, I discuss the basic concepts of DEE, the most used methodologies and current technical advancements, providing examples of applications and perspectives.
Topics: Catalytic Domain; Directed Molecular Evolution; Enzymes; Gene Expression Regulation; Humans; Machine Learning; Models, Molecular; Mutant Proteins; Protein Conformation; Protein Engineering; Recombination, Genetic
PubMed: 32893862
DOI: 10.1042/ETLS20200047 -
Nature Chemical Biology Dec 2021Small molecule drugs form the backbone of modern medicine's therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic... (Review)
Review
Small molecule drugs form the backbone of modern medicine's therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic biology. In this Review, we highlight how resistance mutations have unlocked the potential of small molecule chemical probes to discover new biology. We describe key instances in which resistance mutations and related genetic variants yielded foundational biological insight and categorize these examples on the basis of their role in the discovery of novel molecular mechanisms, protein allostery, physiology and cell signaling. Next, we suggest ways in which emerging technologies can be leveraged to systematically introduce and characterize resistance mutations to catalyze basic biology research and drug discovery. By recognizing how resistance mutations have propelled biological discovery, we can better harness new technologies and maximize the potential of small molecules to advance our understanding of biology and improve human health.
Topics: Alleles; Animals; Diazepam; Drug Discovery; Drug Resistance; Humans; Mutant Proteins; Mutation; Pharmaceutical Preparations; Protein Binding; Protein Conformation; Signal Transduction; Sulfonamides
PubMed: 34799733
DOI: 10.1038/s41589-021-00865-9 -
Cells Oct 2021Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington's, which is caused by increased... (Review)
Review
Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington's, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin.
Topics: Animals; Autophagy; Cell Death; Humans; Huntingtin Protein; Models, Biological; Mutant Proteins; Protein Aggregates; Protein Folding
PubMed: 34831058
DOI: 10.3390/cells10112835 -
Science (New York, N.Y.) Sep 2023Machine-learning algorithm uses structure prediction to spot disease-causing mutations.
Machine-learning algorithm uses structure prediction to spot disease-causing mutations.
Topics: Algorithms; Machine Learning; Mutant Proteins; Protein Conformation; Genetic Variation; Mutation, Missense; Disease; Sequence Analysis, DNA
PubMed: 37725046
DOI: 10.1126/science.adj8672 -
Journal of Computer-aided Molecular... May 2016Mutations in the protein affect not only the structure of protein, but also its function and stability. Prediction of mutant protein stability with accuracy is desired... (Review)
Review
Mutations in the protein affect not only the structure of protein, but also its function and stability. Prediction of mutant protein stability with accuracy is desired for uncovering the molecular aspects of diseases and design of novel proteins. Many advanced computational approaches have been developed over the years, to predict the stability and function of a mutated protein. These approaches based on structure, sequence features and combined features (both structure and sequence features) provide reasonably accurate estimation of the impact of amino acid substitution on stability and function of protein. Recently, consensus tools have been developed by incorporating many tools together, which provide single window results for comparison purpose. In this review, a useful guide for the selection of tools that can be employed in predicting mutated proteins' stability and disease causing capability is provided.
Topics: Algorithms; Amino Acid Substitution; Computational Biology; Mutant Proteins; Mutation; Protein Stability; Sequence Analysis, Protein
PubMed: 27160393
DOI: 10.1007/s10822-016-9914-3 -
Journal of Molecular Biology Oct 2023The study of protein folding plays a crucial role in improving our understanding of protein function and of the relationship between genetics and phenotypes. In...
The study of protein folding plays a crucial role in improving our understanding of protein function and of the relationship between genetics and phenotypes. In particular, understanding the thermodynamics and kinetics of the folding process is important for uncovering the mechanisms behind human disorders caused by protein misfolding. To address this issue, it is essential to collect and curate experimental kinetic and thermodynamic data on protein folding. K-Pro is a new database designed for collecting and storing experimental kinetic data on monomeric proteins, with a two-state folding mechanism. With 1,529 records from 62 proteins corresponding to 65 structures, K-Pro contains various kinetic parameters such as the logarithm of the folding and unfolding rates, Tanford's β and the ϕ values. When available, the database also includes thermodynamic parameters associated with the kinetic data. K-Pro features a user-friendly interface that allows browsing and downloading kinetic data of interest. The graphical interface provides a visual representation of the protein and mutants, and it is cross-linked to key databases such as PDB, UniProt, and PubMed. K-Pro is open and freely accessible through https://folding.biofold.org/k-pro and supports the latest versions of popular browsers.
Topics: Humans; Databases, Protein; Kinetics; Protein Denaturation; Protein Folding; Proteins; Thermodynamics; Mutant Proteins
PubMed: 37625584
DOI: 10.1016/j.jmb.2023.168245 -
Applied Microbiology and Biotechnology Oct 2019β-N-Acetylhexosaminidases (EC 3.2.1.52) are a unique family of glycoside hydrolases with dual substrate specificity and a particular reaction mechanism. Though... (Review)
Review
β-N-Acetylhexosaminidases (EC 3.2.1.52) are a unique family of glycoside hydrolases with dual substrate specificity and a particular reaction mechanism. Though hydrolytic enzymes per se, their good stability, easy recombinant production, absolute stereoselectivity, and a broad substrate specificity predestine these enzymes for challenging applications in carbohydrate synthesis. This mini-review aims to demonstrate the catalytic potential of β-N-acetylhexosaminidases in a range of unusual reactions, processing of unnatural substrates, formation of unexpected products, and demanding reaction designs. The use of unconventional media can considerably alter the progress of transglycosylation reactions. By means of site-directed mutagenesis, novel catalytic machineries can be constructed. Glycosylation of difficult substrates such as sugar nucleotides was accomplished, and the range of afforded glycosidic bonds comprises unique non-reducing sugars. Specific functional groups may be tolerated in the substrate molecule, which makes β-N-acetylhexosaminidases invaluable allies in difficult synthetic problems.
Topics: Biocatalysis; Glycosylation; Mutant Proteins; beta-N-Acetylhexosaminidases
PubMed: 31401752
DOI: 10.1007/s00253-019-10065-0 -
Current Topics in Medicinal Chemistry 2018Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH1 and IDH2 regulate... (Review)
Review
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH1 and IDH2 regulate several cellular processes, including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumors, including gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and IDH2 mutations involve a gain in neomorphic activity that catalyzes αKG conversion to (R)-2- hydroxyglutarate ((R)-2HG). IDH mutation-mediated accumulation of (R)-2HG results in epigenetic dysregulation, altered gene expression, and a block in cellular differentiation. Targeting mutant IDH by development of small molecule inhibitors is a rapidly emerging therapeutic approach as evidenced by the recent approval of the first selective mutant IDH2 inhibitor AG-221 (enasidenib) for the treatment of IDH2-mutated AML. This review will focus on mutant isocitrate dehydrogenase as a therapeutic drug target and provides an update on selective and pan-mutant IDH1/2 inhibitors in clinical trials and other mutant IDH inhibitors that are under development.
Topics: Antineoplastic Agents; Biocatalysis; Enzyme Inhibitors; Humans; Isocitrate Dehydrogenase; Molecular Structure; Mutant Proteins; Mutation; Neoplasms
PubMed: 29773061
DOI: 10.2174/1568026618666180518091144