Variable‐temperature NMR studies of thyroid hormone conformations

Gale, Douglas J.; Craik, David J.; Brownlee, Robert T. C.

doi:10.1002/mrc.1260260402

Cited by 9 publications

(11 citation statements)

References 10 publications

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“…The conformational flexibility and internal dynamics in thyroid hormones in solution have been studied earlier by NMR spectroscopy. − Similar to the three-dimensional structures of thyroid hormones observed in the X-ray structures, these studies also indicated the roughly perpendicular arrangement of the two iodinated rings and the rapid movement of the phenolic ring about the diphenyl ether linkage. As discussed earlier, rotation of the phenolic ring about the O3–C1′ bond in T3 gives rise to the formation of proximal and distal conformers.…”

Section: Resultsmentioning

confidence: 52%

Conformational Flexibility and Halogen Bonding in Thyroid Hormones and Their Metabolites

Mondal

Mugesh

2016

Crystal Growth & Design

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Iodothyronamines (TAMs) are endogenous thyroid hormone (TH) metabolites, which are proposed to be biosynthesized by decarboxylation of the β-alanine side chain of THs. Iodothyronine deiodinases (DIOs) mediate phenolic and tyrosyl ring deiodinations of thyroid hormones and play an important role in thyroid hormone homeostasis. These enzymes also accept iodothyronamines as substrates for deiodination, but the binding affinities of TAMs to DIOs are lower than that of THs. In this paper, we report, for the first time, the formation of halogen bonding in various iodothyronamines by using single crystal X-ray studies. We also describe the conformational changes that take place in the structures of THs and TAMs upon deiodination. Density functional theory calculations were performed to understand the halogen bonded assembly and their biological implications.

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Section: Resultsmentioning

confidence: 52%

Conformational Flexibility and Halogen Bonding in Thyroid Hormones and Their Metabolites

Mondal

Mugesh

2016

Crystal Growth & Design

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“…When a series of variable temperature spectra was recorded to measure the energy barrier for rotation about the ether linkage of T4 and T3, an unexpected separation of the inner ring H2,6 resonance was observed, in addition to the expected separation of the H2‘,6‘ resonance that had been reported earlier in some thyroid hormone analogues . The origin of this phenomenon was not identified, but it suggests the presence of more complicated internal motions than simple rotation of the outer ring.…”

Section: Introductionmentioning

confidence: 79%

“…Previous variable temperature studies at 300 and 400 MHz have shown that the H2′,6′ resonance of thyroxine observed at room temperature is an averaged signal resulting from the rapid exchange of proximal and distal environments and that the two protons yield separate signals at low temperature. 8 The focus in the previous study was on the barrier to rotation of the outer ring, which was determined from a line shape analysis of the coalescing H2′ and H6′ resonances, but at temperatures just above the freezing point of methanol, partial separation of the H2,6 inner ring resonances was also reported. The separation of a resonance due to ortho protons in a substituted benzene derivative is somewhat unusual and is further investigated in the current study.…”

Section: Resultsmentioning

confidence: 99%

“…Of 21 different structures of thyroid hormones and analogues, 10 are in the cisoid form and 11 in the transoid. 7 In previous studies 8 it has been established that the barrier to interconversion of H2′ and H6′ is 36 kJ mol -1 and that the likely mechanism by which this occurs is concerted rotation of φ and φ′, as illustrated in Figure 10. 16 A consequence of such a motion is that it inter-converts cisoid and transoid forms, if the conformation of the alanyl side chain remains fixed.…”

Section: Discussionmentioning

confidence: 97%

“…The outer ring proton which is proximal to the inner ring is upfield of the distal proton, due to a significant ring current shift. For T4, T3, and several analogues , the barrier to the conformational exchange of H2‘ and H6‘ ranges from 33 to 38 kJ mol -1 .

2 Interconversion of the distal and proximal protons of T4.…”

Section: Introductionmentioning

confidence: 99%

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Conformational Dynamics of Thyroid Hormones by Variable Temperature Nuclear Magnetic Resonance: The Role of Side Chain Rotations and Cisoid/Transoid Interconversions

Duggan

Craik

1997

J. Med. Chem.

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1H NMR spectra of the thyroid hormone thyroxine recorded at low temperature and high field show splitting into two peaks of the resonance due to the H2,6 protons of the inner (tyrosyl) ring. A single resonance is observed in 600 MHz spectra at temperatures above 185 K. An analysis of the line shape as a function of temperature shows that the coalescence phenomenon is due to an exchange process with a barrier of 37 kJ mol-1. This is identical to the barrier for coalescence of the H2',6' protons of the outer (phenolic) ring reported previously for the thyroid hormones and their analogues. It is proposed that the separate peaks at low temperature are due to resonances for H2,6 in cisoid and transoid conformers which are populated in approximately equal populations. These two peaks are averaged resonances for the individual H2 and H6 protons. Conversion of cisoid to transoid forms can occur via rotation of either the alanyl side chain or the outer ring, from one face of the inner ring to the other. It is proposed that the latter process is the one responsible for the observed coalescence phenomenon. The barrier to rotation of the alanyl side chain is > or = 37 kJ mol-1, which is significantly larger than has previously been reported for Csp2-Csp3 bonds in other Ph-CH2-X systems. The recent crystal structure of a hormone agonist bound to the ligand-binding domain of the rat thyroid hormone receptor (Wagner et al. Nature 1995, 378, 690-697) shows the transoid form to be the bound conformation. The significant energy barrier to cisoid/transoid interconversion determined in the current study combined with the tight fit of the hormone to its receptor suggests that interconversion between the forms cannot occur at the receptor site but that selection for the preferred bound form occurs from the 50% population of the transoid form in solution.

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NMRand Drug Discovery

Craik

Clark

2003

Burger's Medicinal Chemistry and Drug Discovery

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In this chapter we give an overview of the two major approaches used in NMR and drug discovery: structure‐based design and NMR‐based screening. Combined with the more traditional uses of NMR in medicinal chemistry, they demonstrate the versatility of NMR as a tool for drug discovery. Structure‐based design is considered in two parts, ligand‐based design and receptor‐based design. In the former, NMR provides information on structure elucidation of drug leads, conformational analysis, charge state, tautomeric equilibria, and molecular dynamics and assists in the development of pharmacophore models. In receptor‐based design NMR allows the structures of macromolecular drug targets to be determined and their interactions with ligands to be elucidated. NMR‐based screening is a newer application of NMR technology in drug discovery but it is showing great promise as a tool for lead generation and optimization. Screening approaches based on chemical‐shift perturbation, magnetization transfer, diffusion, relaxation, NOEs, and spin labels are described. The utility of NMR has been enhanced over the last decade by developments in both instruments and methodology. On the instrumental side, increases in magnetic field strengths and the development of cryoprobes have increased sensitivity. Linkages of NMR to liquid chromatography and/or mass spectrometry have increased versatility. On the methods front there have been a range of new approaches discovered that will enhance the study of larger molecular complexes. Advances in protein expression and labeling have played a major role in stimulating the development of new NMR pulse sequences to extract information from such complexes.

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Variable‐temperature NMR studies of thyroid hormone conformations

Cited by 9 publications

References 10 publications

Conformational Flexibility and Halogen Bonding in Thyroid Hormones and Their Metabolites

Conformational Flexibility and Halogen Bonding in Thyroid Hormones and Their Metabolites

Conformational Dynamics of Thyroid Hormones by Variable Temperature Nuclear Magnetic Resonance: The Role of Side Chain Rotations and Cisoid/Transoid Interconversions

NMRand Drug Discovery

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