TY - JOUR
T1 - Sodium/Iodide Symporter Metastable Intermediates Provide Insights into Conformational Transition between Principal Thermodynamic States
AU - Chakrabarti, Mayukh
AU - Amzel, L. Mario
AU - Lau, Albert Y.
N1 - Funding Information:
This research was supported in part by the National Institutes of Health grants GM114250-05 (to Nancy Carrasco & L.M.A), GM114250-06 (to Nancy Carrasco & Mario A. Bianchet), and T32GM135131 (to M.C.).
Funding Information:
We thank Dr. Mario A. Bianchet for helpful advice and discussions. We used CPU and GPU resources and scientific computing services at the Maryland Advanced Research Computing Center (MARCC) and Advanced Research Computing at Hopkins (ARCH), both at Johns Hopkins University. This research was supported in part by the National Institutes of Health grants GM114250-05 (to Nancy Carrasco & L.M.A), GM114250-06 (to Nancy Carrasco & Mario A. Bianchet), and T32GM135131 (to M.C.).
Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/2/23
Y1 - 2023/2/23
N2 - The Sodium/Iodide Symporter (NIS), a 13-helix transmembrane protein found in the thyroid and other tissues, transports iodide, a required constituent of thyroid hormones T3 and T4. Despite extensive experimental information and clinical data, structural details of the intermediate microstates comprising the conformational transition of NIS between its inwardly and outwardly open states remain unresolved. We present data from a combination of enhanced sampling and transition path molecular dynamics (MD) simulations that elucidate the principal intermediate states comprising the inwardly to outwardly open transition of fully bound and apo NIS under an enforced ionic gradient. Our findings suggest that in both the absence and presence of bound physiological ions, NIS principally occupies a proximally inward to inwardly open state. When fully bound, NIS is also found to occupy a rare “inwardly occluded” state. The results of this work provide novel insight into the populations of NIS intermediates and the free energy landscape comprising the conformational transition, adding to a mechanistic understanding of NIS ion transport. Moreover, the knowledge gained from this approach can serve as a basis for studies of NIS mutants to target therapeutic interventions.
AB - The Sodium/Iodide Symporter (NIS), a 13-helix transmembrane protein found in the thyroid and other tissues, transports iodide, a required constituent of thyroid hormones T3 and T4. Despite extensive experimental information and clinical data, structural details of the intermediate microstates comprising the conformational transition of NIS between its inwardly and outwardly open states remain unresolved. We present data from a combination of enhanced sampling and transition path molecular dynamics (MD) simulations that elucidate the principal intermediate states comprising the inwardly to outwardly open transition of fully bound and apo NIS under an enforced ionic gradient. Our findings suggest that in both the absence and presence of bound physiological ions, NIS principally occupies a proximally inward to inwardly open state. When fully bound, NIS is also found to occupy a rare “inwardly occluded” state. The results of this work provide novel insight into the populations of NIS intermediates and the free energy landscape comprising the conformational transition, adding to a mechanistic understanding of NIS ion transport. Moreover, the knowledge gained from this approach can serve as a basis for studies of NIS mutants to target therapeutic interventions.
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U2 - 10.1021/acs.jpcb.2c07604
DO - 10.1021/acs.jpcb.2c07604
M3 - Article
C2 - 36758032
AN - SCOPUS:85148006404
SN - 1520-6106
VL - 127
SP - 1540
EP - 1551
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 7
ER -