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Agonist-induced conformational chang...

Huang, Wei.

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Agonist-induced conformational changes in TRH receptor: A disulfide cross-linking and molecular modeling approach.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Agonist-induced conformational changes in TRH receptor: A disulfide cross-linking and molecular modeling approach./
Author:	Huang, Wei.
Description:	216 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-08, Section: B, page: 3761.
Contained By:	Dissertation Abstracts International64-08B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3099958

Agonist-induced conformational changes in TRH receptor: A disulfide cross-linking and molecular modeling approach.
Huang, Wei.

Agonist-induced conformational changes in TRH receptor: A disulfide cross-linking and molecular modeling approach. - 216 p.

Source: Dissertation Abstracts International, Volume: 64-08, Section: B, page: 3761.

Thesis (Ph.D.)--Weill Medical College of Cornell University, 2003.

Thyrotropin-releasing hormone (TRH) is central in regulating the hypothalamic-pituitary-thyroid axis. The action of TRH is mediated by TRHR receptor subtype-1 (TRH-R1) on the surface receptors on anterior pituitary membrane. TRH-R1 belongs to the family A G protein-coupled receptors (GPCRs). It transduces the TRH-binding to intracellular signaling cascades mainly through Gq/11. In our attempt to uncover the molecular mechanism for its activation, we implemented a combination of disulfide cross-linking and molecular modeling approaches to probe the TRH-induced conformational changes in the transmembrane helices (TMHs).Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Agonist-induced conformational changes in TRH receptor: A disulfide cross-linking and molecular modeling approach.
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035 $a (UnM)AAI3099958
035 $a AAI3099958
040 $a UnM $c UnM
100 1 $a Huang, Wei. $3 1023420
245 1 0 $a Agonist-induced conformational changes in TRH receptor: A disulfide cross-linking and molecular modeling approach.
300 $a 216 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-08, Section: B, page: 3761.
500 $a Adviser: Marvin C. Gershengorn.
502 $a Thesis (Ph.D.)--Weill Medical College of Cornell University, 2003.
520 $a Thyrotropin-releasing hormone (TRH) is central in regulating the hypothalamic-pituitary-thyroid axis. The action of TRH is mediated by TRHR receptor subtype-1 (TRH-R1) on the surface receptors on anterior pituitary membrane. TRH-R1 belongs to the family A G protein-coupled receptors (GPCRs). It transduces the TRH-binding to intracellular signaling cascades mainly through Gq/11. In our attempt to uncover the molecular mechanism for its activation, we implemented a combination of disulfide cross-linking and molecular modeling approaches to probe the TRH-induced conformational changes in the transmembrane helices (TMHs).
520 $a This method, which is based on the probability that two structurally adjacent cysteines will form a disulfide bond under oxidative condition, has been utilized to study the proximity of the endogenous cysteines. The proximity of Cys36 to Cys305/308, and the TRH-induced decreases in this proximity were identified.
520 $a It was also applied to assess TRH-induced conformational changes between TMH5 and TMH6 with 16 double-cysteine mutants, each possess one engineered cysteine at the cytoplasmic end of TMH5 and the other at that of extents of disulfide formation, which were inhibited by TRH. T265C/Y211C and T265C/ G212C exhibited cross-linking upon TRH-binding, and diminished extents without TRH. These values were consistent with the hypothesis that TRH induced separation of TMH5 and TMH6 at the cytoplasmic ends.
520 $a A refined molecular model of TRH-R1, in which a lipid bilayer was constructed, was shown to be in better agreement with experimental findings than previous model. In silico mutagenesis also confirmed this findings. The remaining discrepancies between experiments and models suggested further refinements are needed.
520 $a The combination of experiments and modeling provides a detailed activation model in which TRH binding causes a rotation of the cytoplasmic end of TMH6 and a tilting away of that of TMH5. These conformational changes likely change the conformation of the adjacent intracellular loop3, an important region for G protein coupling.
590 $a School code: 0967.
650 4 $a Health Sciences, Pharmacology. $3 1017717
650 4 $a Biophysics, General. $3 1019105
650 4 $a Chemistry, Biochemistry. $3 1017722
690 $a 0419
690 $a 0786
690 $a 0487
710 2 0 $a Weill Medical College of Cornell University. $3 1021736
773 0 $t Dissertation Abstracts International $g 64-08B.
790 1 0 $a Gershengorn, Marvin C., $e advisor
790 $a 0967
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3099958