The human sodium iodide symporter (hNIS) is a theranostic reporter gene which concentrates several clinically approved SPECT and PET radiotracers and plays an essential role for the synthesis of thyroid hormones as an iodide transporter in the thyroid gland. Development of hNIS mutants which could enhance translocation of the desired imaging ions is currently underway. Unfortunately, it is hindered by lack of understanding of the 3D organization of hNIS and its relation to anion transport. There are no known crystal structures of hNIS in any of its conformational states. Homology modeling can be very effective in such situations; however, the low sequence identity between hNIS and relevant secondary transporters with available experimental structures makes the choice of a template and the generation of 3D models nontrivial. Here, we report a combined application of homology modeling and molecular dynamics refining of the hNIS structure in its semioccluded state. The modeling was based on templates from the LeuT-fold protein family and was done with emphasis on the refinement of the substrate-ion binding pocket. The consensus model developed in this work is compared to available biophysical and biochemical experimental data for a number of different LeuT-fold proteins. Some functionally important residues contributing to the formation of putative binding sites and permeation pathways for the cotransported Na+ ions and I- substrate were identified. The model predictions were experimentally tested by generation of mutant versions of hNIS and measurement of relative (to WT hNIS) I-125(-) uptake of 35 hNIS variants.
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Khelashvili, George
;
Schmidt, Solveig Gaarde
论文数: 0引用数: 0
h-index: 0
机构:
Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, DenmarkCornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Schmidt, Solveig Gaarde
;
Shi, Lei
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
NIDA, Computat Chem & Mol Biophys Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Shi, Lei
;
Javitch, Jonathan A.
论文数: 0引用数: 0
h-index: 0
机构:
Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA
Columbia Univ Coll Phys & Surg, Dept Pharmacol, 630 W 168th St, New York, NY 10032 USA
New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Javitch, Jonathan A.
;
Gether, Ulrik
论文数: 0引用数: 0
h-index: 0
机构:
Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, DenmarkCornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Gether, Ulrik
;
Loland, Claus J.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, DenmarkCornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Loland, Claus J.
;
Weinstein, Harel
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
Last, Nicholas B.
;
Kolmakova-Partensky, Ludmila
论文数: 0引用数: 0
h-index: 0
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
Kolmakova-Partensky, Ludmila
;
Shane, Tania
论文数: 0引用数: 0
h-index: 0
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
Shane, Tania
;
Miller, Christopher
论文数: 0引用数: 0
h-index: 0
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
机构:
Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
Univ Michigan, Biophys Program, Ann Arbor, MI 48109 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
Wei, Shuai
;
Buckner, Joshua
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
Univ Michigan, Biophys Program, Ann Arbor, MI 48109 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
Buckner, Joshua
;
Jeong, Jong Cheol
论文数: 0引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Beth Israel Deaconess Canc Ctr, Canc Res Inst, Boston, MA 02215 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
机构:
Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
Univ Michigan, Biophys Program, Ann Arbor, MI 48109 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
LeVine, Michael V.
;
Cuendet, Michel A.
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Cuendet, Michel A.
;
Khelashvili, George
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Khelashvili, George
;
Weinstein, Harel
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Cornell Univ, Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Levy, O
;
De la Vieja, A
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
De la Vieja, A
;
Ginter, CS
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Ginter, CS
;
Riedel, C
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Riedel, C
;
Dai, G
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Dai, G
;
Carrasco, N
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Levy, O
;
Ginter, CS
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Ginter, CS
;
De la Vieja, A
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
De la Vieja, A
;
Levy, D
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Levy, D
;
Carrasco, N
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Khelashvili, George
;
Schmidt, Solveig Gaarde
论文数: 0引用数: 0
h-index: 0
机构:
Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, DenmarkCornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Schmidt, Solveig Gaarde
;
Shi, Lei
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
NIDA, Computat Chem & Mol Biophys Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Shi, Lei
;
Javitch, Jonathan A.
论文数: 0引用数: 0
h-index: 0
机构:
Columbia Univ Coll Phys & Surg, Dept Psychiat, 722 W 168th St, New York, NY 10032 USA
Columbia Univ Coll Phys & Surg, Dept Pharmacol, 630 W 168th St, New York, NY 10032 USA
New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Javitch, Jonathan A.
;
Gether, Ulrik
论文数: 0引用数: 0
h-index: 0
机构:
Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, DenmarkCornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Gether, Ulrik
;
Loland, Claus J.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen N, DenmarkCornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Loland, Claus J.
;
Weinstein, Harel
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
Last, Nicholas B.
;
Kolmakova-Partensky, Ludmila
论文数: 0引用数: 0
h-index: 0
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
Kolmakova-Partensky, Ludmila
;
Shane, Tania
论文数: 0引用数: 0
h-index: 0
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
Shane, Tania
;
Miller, Christopher
论文数: 0引用数: 0
h-index: 0
机构:
Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USABrandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02254 USA
机构:
Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
Univ Michigan, Biophys Program, Ann Arbor, MI 48109 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
Wei, Shuai
;
Buckner, Joshua
论文数: 0引用数: 0
h-index: 0
机构:
Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
Univ Michigan, Biophys Program, Ann Arbor, MI 48109 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
Buckner, Joshua
;
Jeong, Jong Cheol
论文数: 0引用数: 0
h-index: 0
机构:
Harvard Univ, Sch Med, Beth Israel Deaconess Canc Ctr, Canc Res Inst, Boston, MA 02215 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
机构:
Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
Univ Michigan, Biophys Program, Ann Arbor, MI 48109 USAUniv Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
LeVine, Michael V.
;
Cuendet, Michel A.
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Cuendet, Michel A.
;
Khelashvili, George
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Khelashvili, George
;
Weinstein, Harel
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Cornell Univ, Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USACornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Levy, O
;
De la Vieja, A
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
De la Vieja, A
;
Ginter, CS
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Ginter, CS
;
Riedel, C
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Riedel, C
;
Dai, G
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Dai, G
;
Carrasco, N
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Levy, O
;
Ginter, CS
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Ginter, CS
;
De la Vieja, A
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
De la Vieja, A
;
Levy, D
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
Levy, D
;
Carrasco, N
论文数: 0引用数: 0
h-index: 0
机构:
Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USAYeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA