Monday, March 01, 2021

Never-before-seen antibody binding revealed, informing both liver cancer and antibody design

Good news! Perhaps a breakthrough for better treatments! Cancer is history! Like Covid-19 and HIV/AIDS before, cancer will be defeated! It is only a question of time!

"In structural biology, some molecules are so unusual they can only be captured with a unique set of tools. That’s precisely how a multi-institutional research team led by Salk scientists defined how antibodies can recognize a compound called phosphohistidine—a highly unstable molecule that has been found to play a central role in some forms of cancer, such as liver and breast cancer and neuroblastoma. ...
Previously, ... showed that phosphorylation on the amino acid tyrosine can drive cancer progression, a discovery that led to numerous anticancer drugs. More recently, Hunter turned his attention to phosphorylation of the amino acid histidine (which creates phosphohistidine), suspecting that the process might also play a role in human disease. ...
... developed a suite of antibodies able to bind to phosphohistidine in proteins, and used chemically stabilized phosphohistidine analogues to develop a series of monoclonal antibodies that could recognize these forms. The next step was to understand exactly how the antibodies are able to bind to phosphohistidine. This led ... to collaborate with ... a world-renowned expert in using protein crystallography to define antibody structures, to study the structures of the phosphohistidine antibodies.
“... have been collaborating on this project for the past seven years,” ... “We have obtained new insights into how antibodies can evolve to recognize phosphates linked to proteins, which is very satisfying.”
To find out how phosphohistidine is recognized, they needed to image their antibodies in the act of binding the phosphohistidine, and so formed crystals between each antibody bound to a phosphohistidine peptide. ...
The two types of antibody crystal structures solved by the team revealed exactly how different amino acids are arranged around the phosphohistidine to bind it tightly. Their five structures more than double the number of phospho-specific antibody structures previously reported, and provide insights into how antibodies recognize both the phosphate and the linked histidine. They also reveal at a structural level how the two types of antibody recognize different forms of phosphohistidine, and this will allow the scientists to engineer improved antibodies in the future.​ ..."

"Phosphohistidine (pHis) is a labile posttranslational modification with two isoforms, 1-pHis and 3-pHis, involved in many cellular processes across the kingdoms of life. Due to its lability, it is difficult to study the pHis modification using standard biochemical tools and techniques. ..."

Salk team reveals never-before-seen antibody binding, informing both liver cancer and antibody design - Salk Institute for Biological Studies Multi-institute collaboration uses X-ray crystallography and recombinant antibodies to uncover workings of an elusive molecule central to human health

Here is the link to the referenced paper:

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