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Study uncovers initial folding mechanism of membrane proteins, key in design of new drugs

An international team coordinated by the Interdisciplinary Research Structure in #Biotechnology and #Biomedicine (ERI BioTecMed) of the University of Valencia has proved how the folding of membrane proteins begins before they are inserted into #biological membranes, a fact that has been central to the biochemical research for decades. The study, published in the Nature Communications journal, has been coordinated by Ismael Mingarro, professor of #Biochemistry and #Molecular Biology at the academic institution.

The relevance of this research is that, since membrane proteins are the receptors of more than half of the medicines currently on the market, it is vital to understand their folding to design more efficient drugs. “The fact that the published article, “Transmembrane but not soluble helices fold inside the ribosome tunnel”, explains that the folding begins before the protein has finished synthesizing is a great discovery to understand how these important pharmacological targets adopt their functional structure”, Ismael Mingarro explained.

Proteins, formed by amino acids linked by peptide bonds, are the biological macromolecules that carry out most of the biological functions of living beings. The cellular machine responsible for synthesizing these links are the #ribosomes, which incorporate them according to the order encoded by the RNA (ribonucleic acid) messenger. This chain of amino acids has to adopt the functional structure of the protein. The objective of the research has been to study the folding mechanism of proteins to know how and when adequate folding occurs.

The main novelty this research provides is that the ribosome acts as a platform for the selection of sequences that have to adopt a local (helical) structure in very early stages of protein biosynthesis. This fact implies the ribosome being considered as the first molecular chaperone (which helps the folding of proteins) to make possible the folding of those sequences that have to adopt a helical structure to increase the efficiency of their subsequent integration in the membrane.

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Zika: A Potential Treatment for Brain Cancer?



Zika has largely faded from the news cycle as efforts to control the disease have taken hold and the number of new cases has dropped. Now, it’s back, not as a pending epidemic, but as a potential treatment for brain cancer.

Researchers from the Washington University School of Medicine and the University of California, Santa Barbara have conducted preliminary tests with the virus as a treatment for glioblastoma, a particularly aggressive form of brain cancer.

Zika, which doesn’t carry many risks for adults, was worrisome because it excels at infecting developing brain cells. In fetuses infected while still in the womb, this could lead to microcephaly, a condition marked by severely stunted brain growth. In those with glioblastoma, though, the virus appears to target the very cells responsible for malignant tumor growth.

Still No Cure

Brain tumors are the result of stem cells and neural progenitor cells gone bad, led astray by harmful mutations and growing out of control. In glioblastomas, these cells are hard to cut out completely, as they insinuate themselves into brain tissues, and often recur even after intensive rounds of chemotherapy. Most people with glioblastoma die within two years.

Because brain tumors are formed by stem cells, the Zika virus is an ideal vector for targeting them. Unlike many viruses and compounds, it can cross the blood-brain barrier and, once there, homes in on brain stem cells while leaving mature cells largely alone.

In tests with a modified version of Zika in mice with brain tumors, those exposed to the virus lived longer, although they weren’t cured completely. The researchers also tried out the treatment on samples of human brain tissue in the lab, and found that applying it directly to the cancerous cells caused them to die. Tests in actual humans, however, are still to come. The research was published Tuesday in the Journal of Experimental Medicine.

They also tried out a weakened version of the virus, genetically manipulated to cause fewer harmful side effects in humans, and found that its cancer-fighting abilities weren’t impaired. In fact, when paired with a chemotherapy drug, the treatment worked even better.

This isn’t the first time a virus has been used to fight cancer — the concept is actually fairly widespread, based on the fact that viruses are already well-adapted to penetrate our cells. By either loading them up with tumor-destroying compounds or simply relying on the viruses themselves to kill cancerous cells, researchers have turned several different strains of virus into cancer treatments. Zika itself had already been picked out by UK researchers as a potential brain cancer therapy back in May, although results from those experiments have yet to be released.

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Going Viral: New Cells for Norovirus Production in the Lab

Human norovirus is a major cause of infections that can be particularly dangerous to children and elderly people. Here, a research team found that human induced pluripotent stem cell-derived intestinal epithelial cells allowed for efficient growth of human norovirus in the laboratory, without requiring human tissue or bile. This method raises fewer practical and ethical issues than conventional systems and should prove useful for industrial applications such as testing new potential vaccines

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New Tool for Understanding Enzymes — Google





Yale scientists have taken a novel approach to unraveling the complex structure and regulation of enzymes: They Googled it.

In a new study published online this week in the Proceedings of the National Academy of Sciences, chemistry professor Victor Batista and his colleagues used the Google algorithm PageRank to identify key amino acids in the regulation of a bacterial enzyme essential for most microorganisms.

Enzymes are biomolecules with the unique capability of accelerating chemical reactions that are necessary for life. Although these chemical reactions normally take place in a small portion of the enzyme — known as the active site — the acceleration of the reaction is usually regulated by the binding of a molecule in a different part of the enzyme. The binding position is known as the allosteric site.

Despite decades of study, it is still poorly understood how information is transferred from the allosteric site to the active site. Much of the difficulty has to do with the large number of atoms involved and the great structural flexibility of enzymes.

The Yale team noted that a similar question had been addressed years earlier in the realm of computer science. Researchers at Google had studied the flow of information on the Internet, using PageRank to indicate the importance of each web page in terms of the number and quality of links to other Internet sites.

“This problem is completely analogous to the exchange of information between distant sites that characterizes allosterism,” said Uriel Morzan, a postdoctoral associate in Batista’s lab and co-first author of the study. “By finding out how the information flow through each atom changes with the binding of an allosteric activator to the enzyme, it is possible to find the information channels that are being activated.”

The Yale researchers identified important amino acids for the allosteric process in imidazole glycerol phosphate synthase (IGPS), a bacterial enzyme found in most microorganisms.

The research paves the way for additional experiments related to IGPS activity that may lead to the development of new antibiotics, pesticides, and herbicides.

“It’s exciting that data science methods are starting to percolate into the field of theoretical chemistry, providing new tools for understanding fundamental aspects of catalytic molecular systems when combined with state-of-the-art molecular dynamics simulations and nuclear magnetic resonance (NMR) spectroscopy,” said Batista, who is also a member of the Energy Sciences Institute at Yale’s West Campus.

Co-author J. Patrick Loria, a Yale professor of chemistry and of molecular biophysics and biochemistry, added: “It is the synergistic combination of experimental NMR and computational tools that enables this deeper insight into biological function and demonstrates the importance of collaboration between theorists and experimentalists.”

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