Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

Prabhu, Ninad V.; Perkyns, John S.; Pettitt, B. Montgomery; Hruby, Victor J.

doi:10.1002/(sici)1097-0282(199909)50:3<255::aid-bip3>3.0.co;2-v

Cited by 17 publications

(10 citation statements)

References 97 publications

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“…Molecular modeling studies of α‐MSH have suggested the stacking of the aromatic rings of Phe7 and Trp9 and the orientation of the Arg8 side chain away from the His6, Phe7, and Trp8 side chains 36, 37. In our case, there was no evidence by NMR (NOE and chemical shifts) of stacking of the aromatic rings of Phe/Nal and Trp in compounds 1 , 2 , SHU9119, and MTII.…”

Section: Resultscontrasting

confidence: 59%

¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

et al. 2003

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Melanocortin receptor 4 (MC-4R) is involved in the regulation of energy balance and body weight, and recognizes alpha-, beta-, and gamma-melanocyte stimulating hormones (alpha-, beta-, gamma-MSH). In the search for compounds that regulate food intake and body weight, two synthetic lactam-derivative ligands of alpha-MSH were discovered, MTII and SHU9119. MTII is an agonist and reduces food intake in rats, whereas SHU9119 is an antagonist, and increases food intake and body weight in rats. MTII and SHU9119 are nonselective compounds to MC-4R. To enhance the potency and selectivity at the human MC-4R (hMC-4R), we recently synthesized analogs of SHU9119 (M. A. Bednarek, T. MacNeil, R. N. Kalyani, R. Tang, Van der L. H. T. Ploeg, and D. H. Weinberg, Journal of Medicinal Chemistry, 2001, Vol. 44, pp. 401-409), wherein compound 1 was the most selective for hMC-4R. Replacement of D-Nal by L-Nal in compound 1 made compound 2 weakly active. Comparison of the structures by NMR and molecular modeling of compounds 1 and 2 vs SHU9119 and MTII indicated that, even though they existed as an average of several conformations in solution, there were distinctions in their structures. The gamma-methylene protons of Arg in compound 1 were nonequivalent and shielded probably by the aromatic ring of Nal. The NHi-NHi+1 NOE cross peaks and the temperature coefficients of the amide protons around the "essential core" Nal/Phe7-Arg8-Trp9, required for high affinity and high selectivity at hMC-4R, were indicative of a possible turn structure for these compounds but with differences in their NOE strengths and temperature coefficient values. Molecular modeling of these compounds based on their NMR data showed that the essential core appeared as a "V" shape with two different orientations, one for compound 1 and some of the conformers of SHU9119 and MTII, and the other for compound 2 and some other conformers of SHU9119 and MTII. The remaining conformers of SHU9119 and MTII, which did not map to compound 1 or 2, suggested that they were outside of the hMC-4R binding envelop. These observations may lead to conjectures as to why compound 1 is highly active and selective toward hMC-4R.

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Section: Resultscontrasting

confidence: 59%

¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

et al. 2003

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“…In melanotropins, His titration yields apparent pK around 6, similar to the value obtained for the free amino acid,39 whereas in the dipeptide Ac–His–Trp–NH 2 the found pK was rather higher, around 6.43 16. It is noteworthy that the result suggests the interaction of His 6 with a positively charged group, which is in agreement with structural studies proposing the stacking of Phe 7 and Trp 9 and segregation of His 6 and Arg 8 residues in the external side of the peptide chain 2, 4…”

Section: Resultssupporting

confidence: 87%

“…Among the several α‐MSH analogues, [Nle 4 , D ‐Phe 7 ]α‐MSH (hereafter referred to as NDP‐MSH) has been identified as very potent and long acting in various vertebrate species 3. It has been suggested that the increased potency of the NDP‐MSH derivative is due to a reverse turn‐type structure stabilized by the D ‐Phe 7 substitution in the critical His 6 –Phe 7 –Arg 8 –Trp 9 fragment 4. The presence of Trp residue in position 9 allowed the use of fluorescence spectroscopy in several studies about the hormone and analogues, like the investigation of conformational properties of the peptides in aqueous solution and in interaction with phospholipid bilayers,5 estimation of depth of penetration in dimyristol phosphatidylglycerol (DMPG) vesicles by parallax methods,6 conformation induction by trifluoroethanol,7 verification of the positioning of the peptides in the amphiphile–water interface of reversed micelles,8 determination of intramolecular distance distributions in α‐MSH and NDP‐MSH labeled with o ‐aminobenzoic acid by Förster resonance energy transfer,9 and examination of the structure of analogues containing β‐(2‐naphthyl)‐ D ‐alanine in aqueous solution and in the presence of DMPG vesicles 10…”

Section: Introductionmentioning

confidence: 99%

Acid–base titration of melanocortin peptides: Evidence of Trp rotational conformers interconversion

et al. 2005

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Tryptophantime-resolved fluorescence was used to monitor acid-base titration properties of alpha-melanocyte stimulating hormone (alpha-MSH) and the biologically more potent analog [Nle4, D-Phe7]alpha -MSH (NDP-MSH), labeled or not with the paramagnetic amino acid probe 2,2,6,6-tetramthylpiperidine-N-oxyl-4-amino-4-carboxylic acid (Toac). Global analysis of fluorescence decay profiles measured in the pH range between 2.0 and 11.0 showed that, for each peptide, the data could be well fitted to three lifetimes whose values remained constant. The less populated short lifetime component changed little with pH and was ascribed to Trp g+ chi1 rotamer, in which electron transfer deactivation predominates over fluorescence. The long and intermediate lifetime preexponential factors interconverted along that pH interval and the result was interpreted as due to interconversion between Trp g- and trans chi1 rotamers, driven by conformational changes promoted by modifications in the ionization state of side-chain residues. The differences in the extent of interconversion in alpha-MSH and NDP-MSH are indicative of structural differences between the peptides, while titration curves suggest structural similarities between each peptide and its Toac-labeled species, in aqueous solution. Though less sensitive than fluorescence, the Toac electron spin resonance (ESR) isotropic hyperfine splitting parameter can also monitor the titration of side-chain residues located relatively far from the probe.

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“…Although the important question about the hormone structure–activity relationship has been largely addressed in the melanotropic peptides literature, there is not a consensus about the conformations acquired by both α‐MSH and NDP‐MSH, either in solution or during the membrane–receptor binding. Several studies have indicated that the peptides assume a folded conformation in aqueous medium (a β‐structure or a hairpin loop), comprising the critical 6‐9 fragment, and it was postulated that the increased potency of the NDP‐MSH derivative was due to a reverse turn‐type structure stabilized by the D ‐Phe 7 substitution [7–9]. Otherwise, there are investigations pointing to a rather flexible backbone for α‐MSH in solution, whereas the presence of the D ‐Phe 7 residue favors a more folded structure for the NDP‐MSH analogue [10–12].…”

Section: Introductionmentioning

confidence: 99%

Comparative EPR and fluorescence conformational studies of fully active spin‐labeled melanotropic peptides

et al. 2001

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Similar to melanocyte stimulating hormone (K K-MSH), its potent and long-acting analogue, [Nle 4 , D-Phe 7 ]K K-MSH, when labeled with the paramagnetic amino acid probe 2,2,6,6-tetramethylpiperidine-N-oxyl-4-amino-4-carboxylic acid (Toac), maintains its full biological potency, thus validating any comparative structural investigations between the two labeled peptides. Correlation times, calculated from the electron paramagnetic resonance signal of Toac bound to the peptides, and Toac^Trp distances, estimated from the Toac fluorescence quenching of the Trp residue present in the peptides, indicate a more rigid and folded structure for the potent analogue as compared to the hormone, in aqueous medium. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

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Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

Cited by 17 publications

References 97 publications

¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

Acid–base titration of melanocortin peptides: Evidence of Trp rotational conformers interconversion

Comparative EPR and fluorescence conformational studies of fully active spin‐labeled melanotropic peptides

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Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

Cited by 17 publications

References 97 publications

1H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

1H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

Acid–base titration of melanocortin peptides: Evidence of Trp rotational conformers interconversion

Comparative EPR and fluorescence conformational studies of fully active spin‐labeled melanotropic peptides

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¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)