New study uncovers key differences in allosteric regulation of cAMP receptor proteins in bacteria

Washington, D.C. – A new study, “Identifying Allosteric Hotspots in Mycobacterium tuberculosis cAMP Receptor Protein” published in Biochemistry, provides key insights into how bacterial cAMP receptor proteins (CRPs) respond differently to the ubiquitous signaling molecule, cyclic AMP (cAMP). By comparing the allosteric regulation of Escherichia coli CRP (CRPEcoli) and Mycobacterium tuberculosis CRP (CRPMTB), researchers challenge the assumption that structural similarity predicts functional behavior in allosteric proteins.

This study introduced structurally homologous mutations from previously identified allosteric hotspots in CRPEcoli into CRPMTB to investigate their effects on protein solution structure, stability, and function. The results reveal that despite their structural resemblance, these two proteins from distantly related bacteria do not share identical allosteric behaviors or hotspots in response to molecular signals. These findings underscore the complexity of allosteric regulation and suggest that species-specific mechanisms drive bacterial gene regulation.

Beyond advancing fundamental knowledge of bacterial signaling, this research has potential implications for drug development. Understanding the unique allosteric properties of CRPMTB may inform therapeutic strategies that target transcriptional regulators in M. tuberculosis, a critical factor in bacterial adaptation and pathogenesis.

Implications for Future Research

Future research will explore how evolutionary differences shape allosteric signaling pathways across bacterial species. Understanding the unique regulatory mechanisms of CRP in M. tuberculosis compared to E. coli may provide insights into bacterial adaptation and gene regulation. Additionally, identifying novel regulatory elements within CRP-mediated pathways could inform antimicrobial strategies aimed at selectively disrupting essential bacterial signaling networks, potentially leading to more targeted therapeutic approaches.

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About Institute for Soft Matter Synthesis and Metrology (ISMSM)

The ISMSM at Georgetown University is dedicated to advancing the rapidly growing field of soft matter research, which explores materials that exist between rigid solids and flowing liquids—such as foams, gels, adhesives, lubricants, and biological materials like blood and tissue. These materials, critical to new technologies and commercial applications, behave in fundamentally different ways from traditional solids and liquids.

Our mission is to promote, coordinate, and expand research on soft materials at Georgetown University, with a particular focus on understanding their non-equilibrium behavior, spanning chemical details to coarse-grained modeling. By integrating this understanding through novel measurement techniques, I(SM)² catalyzes innovation in the field. Faculty from Georgetown’s Departments of Physics, Chemistry, Biology, and the Medical School of Medicine program work together to uncover fundamental principles, engineer new materials, and develop precise tools for synthesis and metrology.

About the Researchers

Dr. Rodrigo Maillard is an Associate Professor in the Department of Chemistry and a member of the ISMSM at Georgetown University. He specializes in mechanochemistry and the molecular interactions governing cellular signaling pathways. His research focuses on the dynamics, energetics, and mechanics of macromolecular interactions, particularly in allosteric protein complexes, using advanced spectroscopic, calorimetric, and single-molecule methods such as optical tweezers. Dr. Maillard holds a Ph.D. from The University of Texas Medical Branch and completed postdoctoral research at the University of California, Berkeley. His work provides critical insights into protein function, with implications for drug discovery and bacterial gene regulation.