22 hasil untuk "Gervasio, Francesco L."
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Artikel Jurnal Teks lengkap
Multiple Routes and Milestones in the Folding of HIV–1 Protease Monomer
Proteins fold on a time scale incompatible with a mechanism of random search in conformational space thus indicating that somehow they are guided to the native state through a funneled energetic landscape. At the same time the heterogeneous kinetics suggests the existence of several different…
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Artikel Jurnal Teks lengkap
Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor
[Image: see text] Whether recent updates and new releases of atomistic force fields can model the structural and dynamical properties of proteins containing both folded and partially disordered domains is still unclear. To address this fundamental question, we tested eight recently released force…
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Artikel Jurnal Teks lengkap
Aromatic side-chain flips orchestrate the conformational sampling of functional loops in human histone deacetylase 8
Human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and an important drug-target. High-resolution structures of HDAC8 in complex with substrates or inhibitors are available, which have provided insights into the bound state of HDAC8 and its function. Here, using long all-atom…
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Artikel Jurnal Teks lengkap
Exploring the Structural Basis of Cryptic Pocket Formation Driven by Extensive Protein Conformational Changes in Drug Targets
Allosteric pockets that typically only emerge in the presence of a binder, known as cryptic pockets, can provide an avenue for drug discovery in challenging pharmaceutical targets. However, protein conformations exposing cryptic pockets are generally short-lived and can require significant…
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Artikel Jurnal Teks lengkap
Investigating Cryptic Binding Sites by Molecular Dynamics Simulations
This Account highlights recent advances and discusses major challenges in investigations of cryptic (hidden) binding sites by molecular simulations. Cryptic binding sites are not visible in protein targets crystallized without a ligand and only become visible crystallographically upon binding…
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Artikel Jurnal Teks lengkap
Understanding Ligand Binding Selectivity in a Prototypical GPCR Family
[Image: see text] Adenosine receptors are involved in many pathological conditions and are thus promising drug targets. However, developing drugs that target this GPCR subfamily is a challenging task. A number of drug candidates fail due to lack of selectivity which results in unwanted side…
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Artikel Jurnal Teks lengkap
Insight into the Folding Inhibition of the HIV-1 Protease by a Small Peptide
It has recently been shown that the highly protected segments 24–34 (S(2)) and 83–93 (S(8)) of each of the two 99-mers of human immunodeficiency virus type 1 protease play an essential role in the folding of the monomers, giving rise to the so-called (postcritical) folding nucleus ((FN) minimum…
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Artikel Jurnal Teks lengkap
Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations
p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades…
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Artikel Jurnal Teks lengkap
Combining Machine Learning and Enhanced Sampling Techniques for Efficient and Accurate Calculation of Absolute Binding Free Energies
[Image: see text] Calculating absolute binding free energies is challenging and important. In this paper, we test some recently developed metadynamics-based methods and develop a new combination with a Hamiltonian replica-exchange approach. The methods were tested on 18 chemically diverse ligands…
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Buku
Machine Learning in Biomolecular Simulations
This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from…
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Artikel Jurnal Teks lengkap
Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics
Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the…
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Artikel Jurnal Teks lengkap
The SH2 Domain Regulates c-Abl Kinase Activation by a Cyclin-Like Mechanism and Remodulation of the Hinge Motion
Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2…
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Artikel Jurnal Teks lengkap
Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer
The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely…
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Artikel Jurnal Teks lengkap
Defining the architecture of KPC-2 Carbapenemase: identifying allosteric networks to fight antibiotics resistance
The rise of multi-drug resistance in bacterial pathogens is one of the grand challenges facing medical science. A major concern is the speed of development of β-lactamase-mediated resistance in Gram-negative species, thus putting at risk the efficacy of the most recently approved antibiotics and…
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Artikel Jurnal Teks lengkap
The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study
Fibroblast growth factor receptors (FGFRs) are recognized therapeutic targets in cancer. We here describe insights underpinning the impact of mutations on FGFR1 and FGFR3 kinase activity and drug efficacy, using a combination of computational calculations and experimental approaches including…
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Artikel Jurnal Teks lengkap
Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this…
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Artikel Jurnal Teks lengkap
Protein CoAlation and antioxidant function of coenzyme A in prokaryotic cells
In all living organisms, coenzyme A (CoA) is an essential cofactor with a unique design allowing it to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. It is synthesized in a highly conserved process in prokaryotes and eukaryotes that requires…
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Artikel Jurnal Teks lengkap
Molecular basis of engineered meganuclease targeting of the endogenous human RAG1 locus
Homing endonucleases recognize long target DNA sequences generating an accurate double-strand break that promotes gene targeting through homologous recombination. We have modified the homodimeric I-CreI endonuclease through protein engineering to target a specific DNA sequence within the human RAG1…
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Artikel Jurnal Teks lengkap
The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers
Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we…