期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：15
页码：8222-8224
DOI：10.1073/pnas.2002666117
出版社：The National Academy of Sciences of the United States of America
摘要：It is well known that society faces a conundrum of dealing with antibiotic drug resistance and future deadly bacteria and infections. These battles involve the rise of methicillin-resistant Staphylococcus aureus (1, 2) in hospitals and the general treatment of infections in the population. The process of developing unique and new therapeutics is very active in pharma and research laboratories, and it requires both the identification of new targets and possibly taking a different approach, away from the conventional blockade of an active site. Numerous molecular machines, which have critical function in organisms, utilize allosteric activation as a key mechanistic step. While there have been attempts to target allosteric sites for inhibitor development (3, 4), successful interference with allosteric processes may involve a shift in the inherent dynamics within the machine rather than simply plugging an allosteric binding site (5, 6). In PNAS, Vahidi et al. (7) reveal, through an integrated biophysical, structural, and biochemical study, the role of allosteric communication and dynamics in the large, intact tetradecameric ClpP1P2 protease from Mycobacterium tuberculosis , which is essential for pathogenesis and virulence in tuberculosis. Hence, ClpP1P2 is among the viable antibiotic targets (8). The MtClpP1P2 machine has been studied extensively, but often in components representing a conventional divide-and-conquer strategy. Just as for G-protein–coupled receptors (GPCRs) (9⇓–11), a more comprehensive, multifaceted approach is warranted. As a field of structural biology, we are emerging from a period of separate investigations by a single methodology such as NMR, or crystallography, or electron cryomicroscopy (cryo-EM), or molecular dynamics that may examine components of a machine to a regime where integrated examination of the system is the focus. Utilizing different methodologies, it is possible to overcome and see beyond limitations. For example, the predominant … [↵][1]1Email: byrdra{at}mail.nih.gov. [1]: #xref-corresp-1-1
