• Abundant `secret doors' on human protein

    From ScienceDaily@1:317/3 to All on Wed Apr 6 22:30:40 2022
    Abundant `secret doors' on human proteins could reshape drug discovery
    Identification of hidden vulnerabilities on surface of `undruggable'
    proteins could transform treatment of disease

    Date:
    April 6, 2022
    Source:
    Center for Genomic Regulation
    Summary:
    A groundbreaking new technique reveals the existence of a multitude
    of previously hidden therapeutic targets that control protein
    function and which could, in theory, be targeted to dramatically
    change the course of diseases as varied as dementia, cancer and
    infectious diseases. The approach, which finds that the 'secret
    doors' are abundant and identifiable, could be a game changer
    for drug discovery, leading to safer, smarter and more effective
    medicines. It enables research labs around the world to find
    and exploit vulnerabilities in any protein - - including those
    previously thought 'undruggable'.



    FULL STORY ==========================================================================
    The number of potential therapeutic targets on the surfaces of human
    proteins is much greater than previously thought, according to the
    findings of a new study in the journal Nature.


    ==========================================================================
    A ground-breaking new technique developed by researchers at the Centre
    for Genomic Regulation (CRG) in Barcelona has revealed the existence of
    a multitude of previously secret doors that control protein function and
    which could, in theory, be targeted to dramatically change the course
    of conditions as varied as dementia, cancer and infectious diseases.

    The method, in which tens of thousands of experiments are performed at
    the same time, has been used to chart the first ever map of these elusive targets, also known as allosteric sites, in two of the most common human proteins, revealing they are abundant and identifiable.

    The approach could be a game changer for drug discovery, leading to
    safer, smarter and more effective medicines. It enables research labs
    around the world to find and exploit vulnerabilities in any protein -- including those previously thought 'undruggable'.

    "Not only are these potential therapeutic sites abundant, there is
    evidence they can be manipulated in many different ways. Rather than
    simply switching them on or off, we could modulate their activity like a thermostat. From an engineering perspective, that's striking gold because
    it gives us plenty of space to design 'smart drugs' that target the bad
    and spare the good," explains Andre' Faure, postdoctoral researcher at
    the CRG and co-first author of the paper.

    Proteins play a central role in all living organisms and carry out vital functions such as providing structure, speeding up reactions, acting as messengers or fighting disease. They are made of amino acids, folding
    into countless different shapes in three-dimensional space. The shape
    of a protein is crucial for its function, with just one mistake in an
    amino acid sequence resulting in potentially devastating consequences
    for human health.



    ========================================================================== Allostery is one of the great unsolved mysteries of protein function.

    Allosteric effects occur when a molecule binds to the surface of a
    protein, which in turn causes changes at a distant site in the same
    protein, regulating its function by remote control. Many disease-causing mutations, including numerous cancer drivers, are pathological because
    of their allosteric effects.

    Despite their fundamental importance, allosteric sites are incredibly
    difficult to find. This is because the rules governing how proteins work
    at the atomic level are hidden out of sight. For example, a protein
    might shapeshift in the presence of an incoming molecule, revealing
    hidden pockets deep within its surface that are potentially allosteric
    but not identifiable using conventional structure determination alone.

    Drug hunters have traditionally designed treatments that target a
    protein's active site, the small region where chemical reactions occur or targets are bound. The downside of these drugs, also known as orthosteric drugs, is that active sites of many proteins look very similar and so
    drugs tend to bind and inhibit many different proteins at once, leading
    to potential side effects. In comparison, the specificity of allosteric
    sites means that allosteric drugs are some of the most effective types
    of medication currently available. Many allosteric drugs, which treat
    various conditions ranging from cancer to AIDS to hormone disorders,
    have been discovered by accident.

    The authors of the study addressed this challenge by developing a
    technique called double deep PCA (ddPCA), which they describe as a 'brute
    force experiment'. "We purposefully break things in thousands of different
    ways to build a complete picture of how something works," explains
    ICREA Research Professor Ben Lehner, Coordinator of the Systems Biology programme at the CRG and author of the study. "It's like suspecting
    a faulty spark plug, but instead of only checking that, the mechanic
    dismantles the entire car and checks it piece by piece. By testing ten
    thousand things in one go we identify all the pieces that really matter."
    The method works by changing the amino acids that make up a protein,
    resulting in thousands of different versions of the protein with just
    one or two differences in the sequence. The effects of the mutations
    are then tested all at the same time in living cells in the laboratory.

    "Each cell is a tiny factory making a different version of the protein. In
    a single test tube we have millions of different factories and so we can
    very rapidly test how well all the different versions of a protein work,"
    adds Dr.

    Lehner. The data collected from the experiments is fed into neural
    networks, algorithms that analyze data by mimicking the way the human
    brain operates, which result in comprehensive maps that pinpoint the
    location of allosteric sites on the surfaces of proteins.

    One of the great advantages of the method is that it is an affordable
    technique accessible to any research lab around the world. "It massively simplifies the process needed to find allosteric sites, with the
    technique working at a level of accuracy better than several different
    more expensive and time-consuming lab methods," says Ju'lia Domingo,
    co-first author of the study. "Our hope is that other scientists use the technique to rapidly and comprehensively map the allosteric sites of human proteins one by one." One of the longer-term benefits of the technique
    is its potential to study the function and evolution of proteins. The
    authors of the study believe that, if scaled up, the method could one day result in advances that can precisely predict the properties of proteins
    from their amino acid sequences. If successful, the authors argue this
    would usher in a new era of predictive molecular biology, allowing much
    faster development of new medicine and clean, biology-based industry.

    "While some tools can predict a protein's structure by reading its
    sequence, our method goes one step further by telling us how a protein
    works. This is part of a bigger vision to make biology as engineerable
    as aeroplanes, bridges or computers. We have faced the same challenges
    for over 70 years, but it turns out they are more tractable than
    we previously thought. If we succeed it will open a new field with unprecedented possibilities," concludes Dr. Lehner.


    ========================================================================== Story Source: Materials provided by Center_for_Genomic_Regulation. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Andre J. Faure, Ju'lia Domingo, Jo"rn M. Schmiedel, Cristina
    Hidalgo-
    Carcedo, Guillaume Diss, Ben Lehner. Mapping the energetic and
    allosteric landscapes of protein binding domains. Nature, 2022;
    604 (7904): 175 DOI: 10.1038/s41586-022-04586-4 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220406132418.htm

    --- up 5 weeks, 2 days, 10 hours, 50 minutes
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)