Direct Interaction between an Allosteric Agonist Pepducin and the Chemokine Receptor CXCR4

Janz, Jay M.; Ren, Yulin; Looby, Richard; Kazmi, Manija A.; Sachdev, Pallavi; Grunbeck, Amy; Haggis, Lynn; Chinnapen, Daniel J.‐F.; Lin, Amy; Seibert, Christoph; McMurry, Thomas J.; Carlson, Kenneth E.; Muir, Tom W.; Hunt, S.; Sakmar, Thomas P.

doi:10.1021/ja206661w

Cited by 64 publications

(61 citation statements)

References 27 publications

(25 reference statements)

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“…All peptides were synthesized on Wang resin (Bachem Americas, Torrance, CA, USA) using commercially available Fmoc peptides and L-photoleucine (Life Technologies, Rockford, IL, USA) according to literature procedures [30,31].…”

Section: Methodsmentioning

confidence: 99%

Efficient Covalent Bond Formation in Gas-Phase Peptide–Peptide Ion Complexes with the Photoleucine Stapler

Shaffer

Andrikopoulos

Řezáč

et al. 2016

J. Am. Soc. Mass Spectrom.

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Abstract. Noncovalent complexes of hydrophobic peptides GLLLG and GLLLK with photoleucine (L*) tagged peptides G(L* n L m )K (n = 1,3, m = 2,0) were generated as singly charged ions in the gas phase and probed by photodissociation at 355 nm. Carbene intermediates produced by photodissociative loss of N 2 from the L* diazirine rings underwent insertion into X−H bonds of the target peptide moiety, forming covalent adducts with yields reaching 30%. Gas-phase sequencing of the covalent adducts revealed preferred bond formation at the C-terminal residue of the target peptide. Site-selective carbene insertion was achieved by placing the L* residue in different positions along the photopeptide chain, and the residues in the target peptide undergoing carbene insertion were identified by gas-phase ion sequencing that was aided by specific 13 C labeling. Density functional theory calculations indicated that noncovalent binding to GL*L*L*K resulted in substantial changes of the (GLLLK + H) + ground state conformation. The peptide moieties in [GL*L*LK + GLLLK + H] + ion complexes were held together by hydrogen bonds, whereas dispersion interactions of the nonpolar groups were only secondary in ground-state 0 K structures. Born-Oppenheimer molecular dynamics for 100 ps trajectories of several different conformers at the 310 K laboratory temperature showed that noncovalent complexes developed multiple, residue-specific contacts between the diazirine carbons and GLLLK residues. The calculations pointed to the substantial fluidity of the nonpolar side chains in the complexes. Diazirine photochemistry in combination with Born-Oppenheimer molecular dynamics is a promising tool for investigations of peptide-peptide ion interactions in the gas phase.

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Section: Methodsmentioning

confidence: 99%

Efficient Covalent Bond Formation in Gas-Phase Peptide–Peptide Ion Complexes with the Photoleucine Stapler

Shaffer

Andrikopoulos

Řezáč

et al. 2016

J. Am. Soc. Mass Spectrom.

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“…All peptides were synthesized on Wang resin (Bachem Americas, Torrance, CA, USA) using the Fmoc technology according to literature procedures [9]. Fmoc N-protected photomethionine were prepared according to the literature [10].…”

Section: Methodsmentioning

confidence: 99%

Combining Near-UV Photodissociation with Electron Transfer. Reduction of the Diazirine Ring in a Photomethionine-Labeled Peptide Ion

Shaffer

Marek

Nguyen

et al. 2015

J. Am. Soc. Mass Spectrom.

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Abstract. Electron transfer dissociation of peptide ions with the diazirine-containing residue photomethionine (M*) results in side-chain dissociations by loss of C 3 H 7 N 2 radicals in addition to standard backbone cleavages. The side-chain dissociations are particularly prominent upon activation of long-lived, charge-reduced, cation radicals (GM*GGR + 2H) +• . Investigation of these cation radicals by near-UV photodissociation and collisional activation revealed different fragmentation products and mechanisms resulting from these ion activation modes. The dissociations observed for photomethionine were dramatically different from those previously reported for the lower homologue photoleucine; here, a difference by a single methylene group in the side chain had a large effect on the chemistries of the cation radicals upon ETD and further activation. ETD intermediates and products were probed by tandem 355-nm UV photodissociationcollision induced dissociation and found to contain chromophores that resulted from electron attachment to the diazirine ring. The nature of the newly formed chromophores and ion energetics and kinetics were investigated by electron structure calculations combining ab initio and density functional theory methods and Rice-RamspergerKassel-Marcus (RRKM) theory. The dramatic difference between the dissociations of L* and M* containing peptide cation radicals is explained by electronic effects that play a role in stabilizing critical reaction intermediates and steer the dissociations into kinetically favored reaction channels. In addition, a new alternating UVPD-ETD-UVPD MS 4 experiment is introduced and utilized for ion structure elucidation.

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“…Клетки опухоли и её микроокружения в больших количествах вырабатывают стромальный фактор -хемокин CXCL12/SDF-1, селективный CXCR4-агонист, которому принадлежит ведущая роль в проникновении опухолевых клеток сквозь межтканевые барьеры, что лежит в основе метастазирования опухолей. Вследствие этого, селективные CXCR4-антагонисты, в том числе созданные на основе пепдуцинов, представляют большой интерес как противораковые препараты, действие которых основано на прерывании сигналов, генерируемых активацией рецептора CXCR4 [17,32]. Обнаружено, что пепдуцины, производные ЦП-1 и ЦП-3 рецептора CXCR4, полностью блокируют опосредуемую этим рецептором миграцию клеток лимфоцитарного лейкоза и лимфомы [33].…”

Section: влияние на ангиогенез развитие злокачественных опухолей и мunclassified

“…Таким образом, действие GPCR-пептида может реализовываться только в присутствии гомологичного или комплиментарного ему рецептора и характеризуется рецепторной и тканевой специфичностью, что и было доказано в целом ряде работ [4,[10][11][12][13][14][15][16][17][18]. Специфичность и направленность действия GPCR-пептидов, производных ЦП, а также обнаружение у них активности in vitro и in vivo открыло новые пути для создания на их основе регуляторов гормональных сигнальных систем.…”

Section: Introductionunclassified

Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

Шпаков

Shpakova

2015

BIOMED KHIM

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The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recently data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence, thus, the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show greatest prospects in the development of the new generations of drugs based on GPCR-derived peptides, capable of regulating the important functions of the organism.

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Direct Interaction between an Allosteric Agonist Pepducin and the Chemokine Receptor CXCR4

Cited by 64 publications

References 27 publications

Efficient Covalent Bond Formation in Gas-Phase Peptide–Peptide Ion Complexes with the Photoleucine Stapler

Efficient Covalent Bond Formation in Gas-Phase Peptide–Peptide Ion Complexes with the Photoleucine Stapler

Combining Near-UV Photodissociation with Electron Transfer. Reduction of the Diazirine Ring in a Photomethionine-Labeled Peptide Ion

Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

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