Again and again, we talk about “mutant genes”, when it frequently and almost inevitably gets to protein structure, as in this case. The protein in this case, and in similar cases behaves as an enzyme with an active site. In this case the binding affinity to the coenzyme is so strong that the conversion of GTP is arrested, with downstream consequences. This is somewhat different than other cancers in that the proliferative malignant neoplasia shows up so early. However, in many cancers, depending on tissue, there are progressive metabolic changes, and the mutation(s) come in later transitions. This may be adaptive, and it has to involve local circulation, proinflammatory effects, and mitochondrial function that gives way to reversal from catabolic to anabolic activity (reduced ATP production), which leads to reliance on the Warburgh – Pasteur effect. Further progression results in the cannabolization of peripheral muscle by gluconeogenesis to provide glucose. It is really encouraging to come to a step in the analysis where they have gotten back to protein structure and function in this very complicated disease state.
In a recent breakthrough, a team led by UCSF’s Kevan Shokat was able to exploit a previously unknown “Achilles heel” in K-Ras, part of a family of protein mutations that’s responsible for many cancers. The team discovered a binding site, or “pocket,” where they could design a chemical compound (shown in color) to attach to K-Ras and inhibit its activity. Credit: Shokat Lab
In the epic fight against cancer, a protein called Ras has been one of the arch-villains. First identified in human cancers in the 1980s, this protein is responsible for roughly one-third of all cases, as well as some of the deadliest, including lung, colon and pancreatic cancers.
Ras is a key switch in a multi-step cascade of molecular interactions that take place within cells. Mutations in Ras proteins can result in excessive signals for cells to proliferate and cause them to ignore cues for programmed cell death, leading…
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This was a completely interesting story, especially referring to the Gleevec development, where the drug actually bound to an altered ATP pocket containing the altered amino acid sequence. However that being said there is a real, and economic reason we talk about mutant genes. In dealing with minute and precious tumor samples, we researchers had agreed it was more efficient and economical to deduce the nucleotide sequence, especially given the available tools we had. Even today with MALDI-TOF protein sequencing, it is very difficult to do with miniscule samples in which degradation may have occurred, proteins exist in complex solutions, and proteins can not be efficiently amplified such as DNA and RNA. Therefore using DNA genotyping is an efficient and reliable tool for molecular diagnostics.
However, on another note investigators and companies have been searching for a good ras inhibitor so this may finally offer some advantage for the future development.
The technology has to extend beyond the simple DNA-RNA-protein dogma. I am working on an argument that we are currently in a blind alley.
Here is something that begins to move us forward…
N Leigh Anderson has argued that in the next decade proteomics will take us much farther. The problem has been that you have to automate and have the ability to do large volume of analyses with small sample. But the functionality is really in the proteins. You don’t get much out of genomics, and all cells have the same DNA, but the systems that are affected have different impairment relationships based on their metabolic conditioning – anabolic vs catabolic, and circulatory supply.
Medically, Proteomics Advances Will Rival the Genetics Advances of the Last Ten Years
As the number of medically important proteins increases, the impact will be momentous, according to N. Leigh Anderson
• Seventy percent of the decisions made by physicians today are influenced by results of diagnostic tests, according to N. Leigh Anderson, founder of the Plasma Proteome Institute and CEO of SISCAPA Assay Technologies. Imagine the changes that will come about when future diagnostics tests are more accurate, more useful, more economical, and more accessible to healthcare practitioners. For Dr. Anderson, that’s the promise of proteomics, the study of the structure and function of proteins, the principal constituents of the protoplasm of all cells.
In explaining why proteomics is likely to have such a major impact, Dr. Anderson starts with a major difference between the genetic testing common today, and the proteomic testing that is fast coming on the scene. “Most genetic tests are aimed at measuring something that’s constant in a person over his or her entire lifetime. These tests provide information on the probability of something happening, and they can help us understand the basis of various diseases and their potential risks. What’s missing is, a genetic test is not going to tell you what’s happening to you right now.”
He goes on to say that molecular markers, accessible through proteomic testing, do tell what’s happening now. “Defects in proteins underlie most of disease, and that’s because the business end of biology involves proteins. They’re the molecular machines that manage all the chemical reactions in our bodies. It’s proteins that send out signals and provide movement in muscles, and it’s proteins that form a lot of the body’s structures.”
85% or more of the publications we are seeing get into proteins, isoforms, and isozymes. The heart, skeletal and smooth muscle are energy transducers. The endocrine organs are biosynthesizers. The liver is a synthesizer, but also does detox. The liver has a dual blood supply, and only have of the circulation is the hepatic artery. A Zahn infarct doesn’t come easily!
A study by researchers at IRB Barcelona reveals the existence of information highways that connect and correlate distant sites within a single protein.
Proteins are chains of amino acids that, when folded into certain structural patterns and also when unfolded, exert functions within cells. Proteins receive signals that are transmitted from one to the next and that are essential for life. However, within a given protein, are there “highways” along which the signals travel, like a in a relay event? That is to say, how is the information transmitted in a given protein? “This is one of the key questions in biophysics,” says Xavier Salvatella, ICREA Professor at the Institute for Research in Biomedicine (IRB Barcelona) and head of the Molecular Biophysics Lab.
The most recent study in this field published today in Nature Communications, in collaboration with Modesto Orozco, an expert in biocomputational simulations who also works at IRB Barcelona, shows that the transmission of information over large distances occurs within proteins. This transmission has been observed and demonstrated for all proteins containing beta sheets, one of two structural patterns that folded proteins adopt.
“We are discovering the information transmission pathways inside proteins and this concept, which we have validated for one kind of protein structural motif, allows us to speculate that proteins have many valid surfaces on which a drug can act,” relates Salvatella.
The team of scientists have discovered how the motions of various parts of proteins, although physically far apart, are correlated. “The same thing happens to proteins as happens to the choreography of ballet dancers, where the movements of the participants are interconnected in spite of being physically apart. If the first one lifts an arm, the last one lifts an arm too,” describes the researcher.
A gold mine for drug discovery
Drugs act on a certain site or active domain of a target protein in a given disease. In most infectious diseases and in cancer, one of the problems is that the site where the drug interacts evolves and mutates and the drug is rendered inefficient. The concept, now validated by IRB Barcelona researchers, allows one to think that the site where the drug was headed is equally as valid as any other point along the transmission pathway.
“If this were this case – which is what our data show – we would be able to find many sites within the structure of a protein that would be equally or more efficient at interacting with a drug. Sites that, although lying far from the key or functional site of the protein, would have the same effect,” argues Salvatella.
The scientist goes on to explain that there are already many drugs that act at sites that are not the actives sites but that these drugs have been discovered by serendipity, through massive screenings of molecules and observing that they bound to an unexpected site. “This system is clearly not efficient. We have to be able to organise it and if we manage to do this, then we will have a potent way to discover new drugs,” explains the researcher.
In addition to furthering the conceptual field, Salvatella is working with proteins of biomedical interest. “We already know enough to study in parallel the pathways of proteins of biomedical interest. If we are successful, we will have discovered a gold mine for drug discovery,” affirms the scientist.
The first authors of the article are the postdoctoral fellows Bryn Fenwick, a former member of Xavier Salvatella’s group, currently at the Scripps Research Institute of California, and Laura Orellana, a former member of Modesto Orozco’s group, who is now at the Science for Life Laboratory at the Royal Institute of Technology in Stockholm. The work has been done within the joint programme in Computational Biology between BSC, CRG and IRB Barcelona.
The article, Correlated motions are a fundamental property of β-sheets, is published in Nature Communications.