Brief Introduction about the Recent Progress in Structural Biology Research
Posted by Jerry Carter on December 2nd, 2020
Structural biology is a branch of molecular biology, biochemistry, and biophysics concerned with the molecular structure of biological macromolecules how they acquire the structures they have, and how alterations in their structures affect their function. (Wikipedia)
This post is a roundup blog telling about the recent advances in structural biology.
A key molecular "machine" called the BAF complex alters the structure of DNA and is frequently mutated in cancer and some other diseases. In a new study, researchers from the Dana-Farber Cancer Institute, Rockefeller University, and the University of Washington in the United States constructed an unprecedented three-dimensional structural model of this complex. They report for the first time a three-dimensional structural "picture" of the first BAF complex in the native state purified directly from human cells, which gives the opportunity to spatially correspond thousands of cancer-related mutations to specific locations of this complex.
In a new study, researchers from the University of Massachusetts Medical School, Harvard University, Thermo Fisher Scientific, and Regeneron Pharmaceuticals found that D614G was more infectious than its ancestral virus in human lung cells, colon cells, and cells that allowed viral infection by ectopic expression of human ACE2 or ACE2 homologs from various mammals (including Chrysanthemum sinensis and Pangolin Malaya). The relevant research results were published online in the journal Cell on September 15, 2020. D614G did not alter the synthesis, processing, or integration of the S protein into SARS-CoV-2 viral particles, but the affinity of D614G for ACE2 was reduced due to the faster dissociation rate.
Evaluation of the S protein trimer by cryo-electron microscopy showed that D614G disrupts the contact between the protomer of the S protein and shifts the conformation of the S protein to a state that is able to bind ACE2, which is thought to be a pathway for the fusion of viral particles with target cell membranes. Consistent with this more open conformation, the neutralizing potency of antibodies targeting the receptor binding domain (RBD) of the S protein was not diminished.
Hallucinogens such as lysergic acid diethylamine (LSD), psilocybin, and mescaline cause severe and often long-lasting hallucinations, but they show great potential in treating serious mental illnesses such as major depression. To fully investigate this potential, scientists need to know how these drugs interact with brain cells at the molecular level to elicit their remarkable biological effects.
In a new study, Dr. Bryan L. Roth of the University of North Carolina at Chapel Hill and Dr. Georgius Skiniotis of Stanford University and colleagues took a big step in this direction. They solved for the first time the high-resolution structure of these hallucinogens when bound to the 5-HT2A serotonin receptor (HTR2A) on the surface of brain cells. The discovery has led to the exploration of more precise compounds that can eliminate hallucinations, but still have strong therapeutic effects. In addition, scientists can effectively change the chemical composition of drugs such as LSD and nakisin, which are hallucinogenic compounds in mushrooms and have been granted a breakthrough position by the US Food and Drug Administration (FDA) for the treatment of depression.
In a new study, researchers from the Federal Institute of Technology in Lausanne, Switzerland, and the University of Basel determined cryo-electron microscopic (cryo-EM) structures with a resolution of 3.1 Å when human cGAS is bound to nucleosomes.
CGAS makes extensive contact with the acidic pocket (acidicpatch) and nucleosomal DNA of the histone H2A-H2B heterodimer. Structural and complementary biochemical analyses also revealed that cGAS binds to the second nucleosome in trans. Mechanistically, nucleosome binding locks cGAS in a monomeric state, where steric hindrance inhibits the misactivation of cGAS by genomic DNA. These researchers found that mutations occurring at the cGAS-acidic pocket interface were sufficient to abolish the inhibitory effect of nucleosomes on cGAS in vitro as well as trigger the enzymatic activity of cGAS on genomic DNA in living cells.
In a new study, researchers from the University of Tokyo in Japan, Waseda University, and Rockefeller University in the United States reported the structural basis for this inhibition.
These researchers solved the cryo-electron microscopy (cryo-EM) structure of the human cGAS-nucleosome core particle (cGAS-NCP) complex. In this structure, the two cGAS monomers bridge the two nucleosome core particles (NCP) by binding the acidic pocket (acidicpatch) of H2A-H2B and the nucleosome DNA.
In this configuration, all three known cGAS DNA-binding sites required for cGAS activation are repurposed or inaccessible, and as another prerequisite for cGAS activation, cGAS dimerization is inhibited. Mutating key amino acid residues that link the acidic pockets of cGAS and H2A-H2B together attenuates the inhibition of cGAS activation by nucleosomes.
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About the AuthorJerry Carter
Joined: November 1st, 2019
Articles Posted: 32
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