Academic Journal
Crystallographic and Computational Insights into Isoform-Selective Dynamics in Nitric Oxide Synthase
| العنوان: | Crystallographic and Computational Insights into Isoform-Selective Dynamics in Nitric Oxide Synthase |
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| المؤلفون: | Huiying Li, Christine D. Hardy, Cory T. Reidl, Qing Jing, Fengtian Xue, Maris Cinelli, Richard B. Silverman, Thomas L. Poulos |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | Biophysics, Biochemistry, Cell Biology, Molecular Biology, Neuroscience, Physiology, Pharmacology, Computational Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, nitric oxide synthase, undergo conformational changes, substantial dynamic differences, computational results show, second inhibitor molecule, tighter dimer interface, conserved tyrosine near, subtle structural differences, develop inhibitors selective, nos inhibitor binding, dimer interface, conserved tyrosine, selective inhibitors, structural basis, nos isoforms, changes conformation, selective dynamics, computational methods, computational insights, inhibitor binding |
| الوصف: | In our efforts to develop inhibitors selective for neuronal nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS), we found that nNOS can undergo conformational changes in response to inhibitor binding that does not readily occur in eNOS. One change involves movement of a conserved tyrosine, which hydrogen bonds to one of the heme propionates, but in the presence of an inhibitor, changes conformation, enabling part of the inhibitor to hydrogen bond with the heme propionate. This movement does not occur as readily in eNOS and may account for the reason why these inhibitors bind more tightly to nNOS. A second structural change occurs upon the binding of a second inhibitor molecule to nNOS, displacing the pterin cofactor. Binding of this second site inhibitor requires structural changes at the dimer interface, which also occurs more readily in nNOS than in eNOS. Here, we used a combination of crystallography, mutagenesis, and computational methods to better understand the structural basis for these differences in NOS inhibitor binding. Computational results show that a conserved tyrosine near the primary inhibitor binding site is anchored more tightly in eNOS than in nNOS, allowing for less flexibility of this residue. We also find that the inefficiency of eNOS to bind a second inhibitor molecule is likely due to the tighter dimer interface in eNOS compared with nNOS. This study provides a better understanding of how subtle structural differences in NOS isoforms can result in substantial dynamic differences that can be exploited in the development of isoform-selective inhibitors. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/Crystallographic_and_Computational_Insights_into_Isoform-Selective_Dynamics_in_Nitric_Oxide_Synthase/25308350 |
| DOI: | 10.1021/acs.biochem.3c00601.s001 |
| الاتاحة: | https://doi.org/10.1021/acs.biochem.3c00601.s001 https://figshare.com/articles/journal_contribution/Crystallographic_and_Computational_Insights_into_Isoform-Selective_Dynamics_in_Nitric_Oxide_Synthase/25308350 |
| Rights: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.E6EC9E1D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.biochem.3c00601.s001 |
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