Academic Journal
An Atomistic Understanding of Allosteric Inhibition of Glutamate Racemase: a Dampening of Native Activation Dynamics
| العنوان: | An Atomistic Understanding of Allosteric Inhibition of Glutamate Racemase: a Dampening of Native Activation Dynamics |
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| المؤلفون: | Witkin, Katie R., Vance, Nicholas R., Caldwell, Colleen, Li, Quinn, Yu, Liping, Spies, M. Ashley |
| المصدر: | ChemMedChem ; volume 15, issue 4, page 376-384 ; ISSN 1860-7179 1860-7187 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2020 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | Glutamate racemases (GR) are members of the family of bacterial enzymes known as cofactor‐independent racemases and epimerases and catalyze the stereoinversion of glutamate. D‐amino acids are universally important for the proper construction of viable bacterial cell walls, and thus have been repeatedly validated as attractive targets for novel antimicrobial drug design. Significant aspects of the mechanism of this challenging stereoinversion remain unknown. The current study employs a combination of MD and QM/MM computational approaches to show that the GR from H. pylori must proceed via a pre‐activation step, which is dependent on the enzyme's flexibility. This mechanism is starkly different from previously proposed mechanisms. These findings have immediate pharmaceutical relevance, as the H. pylori GR enzyme is a very attractive allosteric drug target. The results presented in this study offer a distinctly novel understanding of how AstraZeneca's lead series of inhibitors cripple the H. pylori GR's native motions, via prevention of this critical chemical pre‐activation step. Our experimental studies, using SPR, fluorescence and NMR WaterLOGSY, show that H. pylori GR is not inhibited by the uncompetitive mechanism originally put forward by Lundqvist et al.. The current study supports a deep connection between native enzyme motions and chemical reactivity, which has strong relevance to the field of allosteric drug discovery. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/cmdc.201900642 |
| الاتاحة: | http://dx.doi.org/10.1002/cmdc.201900642 https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201900642 https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cmdc.201900642 |
| Rights: | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: | edsbas.9BCF1621 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/cmdc.201900642 |
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