Oxytocin-Receptor Binding:  Why Divalent Metals Are Essential

Liu, Dengfeng; Seuthe, Alexandra B; Ehrler, Oli T.; Zhang, Xiaohua; Wyttenbach, Thomas; Hsu, Jeffrey F; Bowers, Michael T.

doi:10.1021/ja046042v

Cited by 66 publications

(103 citation statements)

References 20 publications

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“…peptide bond of the neutral peptide molecule according to mass spectrometry and molecular dynamics simulation results. 21,25 In Figure 2, (Figure 2d), no observation of the y7-or b6-related fragment ions suggest that the dissociation processes originated from the Asp1 five-membered ring cleavage and the His6-containing cleavage are not activated due to the Ang II binding sites of the Ca 2+ ion. The Ang II binding sites of the Ca 2+ ion were reported to be two carboxyl groups (Asp1 and Phe8) and two peptide carbonyl oxygens (Arg2 and His6) in the NMR experiment.…”

Section: Resultsmentioning

confidence: 97%

Determination of a Binding Site of Cu, Ni, Mg, and Ca Metal Ions with Angiotensin II Peptide by Electrospray Tandem Mass Spectrometry

Kim¹,

Kim²,

Kim³

2010

Bulletin of the Korean Chemical Society

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Angiotensin II (Ang II) is the main active hormone in the renin-angiotensin blood pressure regulation system. 1 Ang II is an octapeptide hormone (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8, DRVYIHPF) that has been studied for several decades in the structure-dependent activity of the biological pathway of the Ang II receptor. [2][3][4][5][6][7][8][9][10][11][12][13] Free Ang II molecular structures in solutions have been investigated with a variety of techniques. The results have been reported as β-turn, random coil, hair-pin and other structures.2-8 The structures of Ang II complexed with a receptor have been reported as a hair-pin or an extended structure in NMR and crystallography studies. [9][10][11][12][13] It is evident that several reports are not consistent with each other and that no clear agreement exists regarding the biologically active structure of Ang II during the biological process.For the study of blood pressure control and metal-peptide interaction, the influences of metal cations on the biological activity of Ang II have been also investigated. , and Ca 2+ ) and the Ang II molecule to explain the biological effect in terms of a gas-phase structural difference. We present the results of a tandem mass spectrometry and multiple mass spectrometry study regarding the interaction of metal ions with the Ang II molecule, the C-terminus amidated Ang II molecule (DRVYIHPF-NH 2 ), and two of its segments: the N-terminus tetrapeptide Asp1-Arg2-Val3-Tyr4-NH2 (DRVY-NH2) and the N-terminus hexapeptide Asp1-Arg2-Val3-Tyr4-Ile5-His6-NH2 (DRVYIH-NH2). Two N-terminus segments are used to confirm the [metal II + Ang II] 2+ complex formation efficiency and the metal binding site. Experimental SectionThe gas-phase [metal II + Ang II] 2+ cation complexes were produced by an electrospray ionization source. The experimental MS/MS and MS/MS/MS spectra for fragmentation pattern analysis were obtained using a Thermo Finnigan LTQ mass spectrometer (Thermo Electron Corp., San Jose, CA, USA). This mass spectrometer is a linear ion trap mass spectrometer equipped with an atmospheric pressure-ionization source. LTQ conditions. The samples were introduced into the electrospray interface by a direct infusion method using a microsyringe pump (SGE, Australia) at a flow rate of 5 µL min. The MS/MS spectra were acquired with experimental conditions of an isolation width of 0.5 -1 mass unit, an activation time of 30 msec and q z = 0.25. In MS/MS or MS/MS/MS mode, the parent ion molecules were manually selected one by one, and each was subjected to collision-induced dissociation (CID).Reagents. Ang II human (96%, Fluka), DRVYIHPF-NH2 (> 90%, Peptron, Daejeon, Korea), DRVY-NH2 (> 90%, Peptron, Daejeon, Korea), DRVYIH-NH2 (> 90%, Peptron, Daejeon, Korea), CuCl 2 ․2H 2 O (99%, Sigma-Aldrich Korea), Ni(NO 5 ) 2 ․ 6H2O (97%, Junsei chemical Co., Tokyo, Japan), CaCl2․2H2O (98%, Daejung Chemical Korea), Mg(NO3)2․6H2O (98%, Junsei chemical Co., Tokyo, Japan), and H2O (HPLC grade, Merck) were used in experiments. Ang II was dissolved in water to...

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Section: Resultsmentioning

confidence: 97%

Determination of a Binding Site of Cu, Ni, Mg, and Ca Metal Ions with Angiotensin II Peptide by Electrospray Tandem Mass Spectrometry

Kim¹,

Kim²,

Kim³

2010

Bulletin of the Korean Chemical Society

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“…Zn 2 + , for example, participates in the activation of the oxytocin receptor binding site by forming a strongly bound octahedral complex in which the metal ion is coordinated with all carbonyl oxygens, leaving the terminal amine nitrogen and side chains free for binding to the target protein. [20] Manganese, in various oxidation states, in photosystem II (PS II) is an interesting example of transition metal ions that exists as the reactive center in biological systems. Clusters of Mn 4 CaO 5 (Mn III , Mn IV and Mn V ) in the oxygen evolving centre (OEC) of PS II participate in water oxidation.…”

Section: Complexes Of Mnmentioning

confidence: 99%

Structures, Unimolecular Fragmentations, and Reactivities of the Self‐Assembled Multimetallic/Peptide Complexes [Mn_n(GlyGly‐H)_2n−1]⁺ and [Mn_n+1(GlyGly‐H)_2n]²⁺

Moghaddam

Fridgen

2016

ChemPhysChem

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Complexes of Mn(2+) with deprotonated GlyGly are investigated by sustained off-resonance irradiation collision-induced dissociation (SORI-CID), infrared multiple-photon dissociation spectroscopy, ion-molecule reactions, and computational methods. Singly [Mnn (GlyGly-H)2n-1 ](+) and doubly [Mnn+1 (GlyGly-H)2n ](2+) charged clusters are formed from aqueous solutions of MnCl2 and GlyGly by electrospray ionization. The most intense ion produced was the singly charged [M2 (GlyGly-H)3 ](+) cluster. Singly charged clusters show extensive fragmentations of small neutral molecules such as water and carbon dioxide as well as dissociation pathways related to the loss of NH2 CHCO and GlyGly. For the doubly charged clusters, however, loss of GlyGly is observed as the main dissociation pathway. Structure elucidation of [Mn3 (GlyGly-H)4 ](2+) clusters has also been done by IRMPD spectroscopy as well as DFT calculations. It is shown that the lowest energy structure of the [Mn3 (GlyGly-H)4 ](2+) cluster is deprotonated at all carboxylic acid groups and metal ions are coordinated with carbonyl oxygen atoms, and that all amine nitrogen atoms are hydrogen bonded to the amide hydrogen. A comparison of the calculated high-spin (sextet) and low-spin (quartet) state structures of [Mn3 (GlyGly-H)4 ](2+) is provided. IRMPD spectroscopic results are in agreement with the lowest energy high-spin structure computed. Also, the gas-phase reactivity of these complexes towards neutral CO and water was investigated. The parent complexes did not add any water or CO, presumably due to saturation at the metal cation. However, once some of the ligand was removed via CO2 laser IRMPD, water was seen to add to the complex. These results are consistent with high-spin Mn(2+) complexes.

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“…10,17 The structure of Ang II has been reported to be S-shaped according to the results of an NMR experiment.…”

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confidence: 99%

DFT Study of the [Cu-Angiotensin II]²⁺Complex Structure

Kim¹,

Kim²

2012

Bulletin of the Korean Chemical Society

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Oxytocin-Receptor Binding: Why Divalent Metals Are Essential

Cited by 66 publications

References 20 publications

Determination of a Binding Site of Cu, Ni, Mg, and Ca Metal Ions with Angiotensin II Peptide by Electrospray Tandem Mass Spectrometry

Determination of a Binding Site of Cu, Ni, Mg, and Ca Metal Ions with Angiotensin II Peptide by Electrospray Tandem Mass Spectrometry

Structures, Unimolecular Fragmentations, and Reactivities of the Self‐Assembled Multimetallic/Peptide Complexes [Mn_n(GlyGly‐H)_2n−1]⁺ and [Mn_n+1(GlyGly‐H)_2n]²⁺

DFT Study of the [Cu-Angiotensin II]²⁺Complex Structure

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Oxytocin-Receptor Binding: Why Divalent Metals Are Essential

Cited by 66 publications

References 20 publications

Determination of a Binding Site of Cu, Ni, Mg, and Ca Metal Ions with Angiotensin II Peptide by Electrospray Tandem Mass Spectrometry

Determination of a Binding Site of Cu, Ni, Mg, and Ca Metal Ions with Angiotensin II Peptide by Electrospray Tandem Mass Spectrometry

Structures, Unimolecular Fragmentations, and Reactivities of the Self‐Assembled Multimetallic/Peptide Complexes [Mnn(GlyGly‐H)2n−1]+ and [Mnn+1(GlyGly‐H)2n]2+

DFT Study of the [Cu-Angiotensin II]2+Complex Structure

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Structures, Unimolecular Fragmentations, and Reactivities of the Self‐Assembled Multimetallic/Peptide Complexes [Mn_n(GlyGly‐H)_2n−1]⁺ and [Mn_n+1(GlyGly‐H)_2n]²⁺

DFT Study of the [Cu-Angiotensin II]²⁺Complex Structure