Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
Processing Request
Insight into tetrodotoxin blockade and resistance mechanisms of Nav1.2 sodium channel by theoretical approaches.
Item request has been placed!
×
Item request cannot be made.
×
![loading](/sites/all/modules/hf_eds/images/loading.gif)
Processing Request
- معلومة اضافية
- نبذة مختصرة :
Nav1.2, a member of voltage‐gated sodium channels (Navs) that are responsible for the generation and propagation of action potentials along the cell membrane, and play a vital role in the process of information transmission within the nervous system and muscle contraction, is preferentially expressed in the central nervous system. As a potent and selective blocker of Navs, tetrodotoxin (TTX) has been extensively studied in biological and chemical sciences, whereas the detailed mechanism by which it blocks nine Nav1 channel subtypes remain elusive. Despite the high structural similarity, the TTX metabolite 4,9‐anhydro‐TTX is 161 times less effective toward the mammalian Nav1.2, which puzzled us to ask a question why such a subtle structural variation results in the largely binding affinity difference. In the current work, an integrated computational strategy, including homology modeling, induced fit docking, explicit‐solvent MD simulations, and free energy calculations, was employed to investigate the binding mechanism and conformational determinants of TTX analogs. Based on the computational results, the H‐bond interactions between C4‐OH and C9‐OH of TTX and the outer ring carboxylates of the selectivity‐filter residues, and the cation–π interaction between the primary amine of guanidinium of TTX and Phe385 determine the difference of their binding affinities. Moreover, the computationally simulations were carried out for the D384N and E945K mutants of hNav1.2‐TTX, and the rank of the predicted binding free energies is in accordance with the experimental data. These observations provide a valuable model to design potent and selective neurotoxins of Nav1.2 and shed light on the blocking mechanism of TTX to sodium channels. [ABSTRACT FROM AUTHOR]
- نبذة مختصرة :
Copyright of Chemical Biology & Drug Design is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
No Comments.