Crystal structures of peptides and modified peptides

Marraud, Michel; Aubry, A.

doi:10.1002/(sici)1097-0282(1996)40:1<45::aid-bip3>3.0.co;2-3

Cited by 81 publications

(64 citation statements)

References 231 publications

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“…In contrast, strategies for construction of 13-hairpins have been less widely explored (27-32). Furthermore, crystallographic examinations have been made only in two-to five-residue acyclic peptides (33)(34)(35)(36)(37)(38)(39)(40). In this report we describe the crystal structure of a designed, synthetic 13-hairpin in an acyclic octapeptide.…”

mentioning

confidence: 99%

A designed beta-hairpin peptide in crystals.

Karle

Awasthi

Balaram

1996

Proc. Natl. Acad. Sci. U.S.A.

168

123

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ABSTRACT13-hairpin structures have been crystallographically characterized only in very short acyclic peptides, in contrast to helices. The structure of the designed ,3-hairpin, t-butoxycarbonyl-Leu-Val-Val-D-Pro-Gly-Leu-Val-Val-OMe in crystals is described. The two independent molecules of the octapeptide fold into almost ideal 13-hairpin conformations with the central D-Pro-Gly segment adopting a Type 1' 13-turn conformation. The definitive characterization of a 13-hairpin has implications for de novo peptide and protein design, particularly for the development of three-and four-stranded 13-sheets.De novo peptide and protein design is based on the ability to construct peptide sequences with predictable folding patterns (1-7). Helices and 13-sheets have been the focus of considerable synthetic attention in attempts to assemble mimics for helical bundles (8-11) and all 83-motifs (12-15). Helix nucleation strategies have been successful in generating both watersoluble helices, using stabilizing side chain interactions (16)(17)(18)(19), and incorporating backbone conformational constraints in hydrophobic helices (20)(21)(22). The ready crystallizability of peptide helices nucleated with a,a-dialkylated amino acids has permitted detailed stereochemical characterization by x-ray diffraction (23-26). In contrast, strategies for construction of 13-hairpins have been less widely explored (27-32). Furthermore, crystallographic examinations have been made only in two-to five-residue acyclic peptides (33)(34)(35)(36)(37)(38)(39)(40). In this report we describe the crystal structure of a designed, synthetic 13-hairpin in an acyclic octapeptide.Analysis of 13-hairpin structures in proteins reveal that such features invariably contain Type II' or I' 13-turns as the nucleating segment of the chain reversal (41-43). We therefore designed the octapeptide t-butoxycarbonyl (Boc)-LeuVal-Val-D-Pro-Gly-Leu-Val-Val-OMe (11) such that the central D-Pro-Gly segment facilitates a Type II' 13-turn conformation. The constraint of pyrrolidine ring formation in D-Pro restricts the value of 4 to +60°+ 20°. The idealized conformational angles for the i+ 1/i+2 residues of a Type II' 13-turn are: 0j+1 = +600, qAj+, = -120°, 4i+2 = -80°, and q/i+2 = 0°( 44, 45). The valine-rich arms are expected to favor extended strand conformations in view of the established propensity of 13-branched residues to occur in 13-sheets in proteins (46-48). EXPERIMENTAL METHODSThe peptide was synthesized by conventional solution phase procedures and purified by medium pressure liquid chromatography on a C18 column (40-60 microns), followed by HPLC purification on a C18 column (10 microns) using methanolwater gradients. The peptide was fully characterized by 400 MHz 'H NMR (49).Colorless crystals in the form of very thin plates were grown by slow evaporation from a CH30H solution, to which a small amount of water was added. Almost all the crystals were composites in the form of a stack of several thin wafers. The crystal selected for data collection had a slightly sp...

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mentioning

confidence: 99%

A designed beta-hairpin peptide in crystals.

Karle

Awasthi

Balaram

1996

Proc. Natl. Acad. Sci. U.S.A.

168

123

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“…The latter was hydrolyzed (3N HCl (MeCN/H 2 O 1:1)) to give peptide acid 19. The Z group of Z-Phe-Aib-OtBu (20) was removed, and the subsequent coupling with 19 by using of PyAOP provided hexapeptide ZGly-Aib-Pro-Aib-Phe-Aib-OtBu (21) in moderate yield. After the removal of the protecting groups, the linear precursor was subjected to cyclization, but both DEPBT and PyBOP, failed to give cyclo(Gly-Aib-Pro-Aib-Phe-Aib) (22).…”

Section: Methodsmentioning

confidence: 99%

“…As a consequence of this reduced conformational space, Pro strongly prefers the (i + 1)-position of most β-turns [19]. In Pro-Xaa sequences, the preference for a certain type of β-turn conformation depends on the structure of the Xaa residue, such as L/D configuration and side chain nature, as well as on the environment (solid or solution state, solvent polarity) [20].…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Cyclohexapeptides Containing Pro and Aib Residues.

2005

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Cyclization reactions on hexapeptides containing several alpha-aminoisobutyric acid (= 2-amino-2-methylpropanoic acid; Aib) residues and the turn-promoting glycine (Gly) and proline (Pro) residues were investigated. Eight linear hexapeptides were synthesized, and their cyclization was attempted with various coupling reagents. The macrolactamization step proved to be difficult since only three hexapeptides could be cyclized. Two of these latter peptides were the linear precursors of the same cyclic hexapeptide, cyclo(Aib-Aib-Phe-Pro-Aib-Gly) (1). Surprisingly, they gave 1 in almost the same yield. Thus, 1 was obtained in 35% yield upon ring closure at the Phe/Pro site by using DEPBT as the coupling reagent, whereas the cyclization at the Aib/Phe site led to 1 in 28 and 34% yield by using PyAOP and DEPC, respectively (DEPBT = 3-[(diethoxyphosphoryl)oxy]-1,2,3-benzotriazin-4(3H)-one, PyAOP = (1H-7-azabenzotriazol-1-yloxy)tripyrroli-din-1-ylphosphonium hexafluorophosphate, DEPC = diethyl phosphorocyanidate). Another cyclic hexapeptide, cyclo(Aib-Aib-Gly-Aib-Pro-Gly) (2) was prepared in 34% yield when DEPC was used in the cyclization step. The solid-state conformation of 1 was established by X-ray crystallography. 2 Cyclization reactions on hexapeptides containing several Aib residues and the turn promoting Gly and Pro residues were investigated. Eight linear hexapeptides were synthesized and their cyclization was attempted using various coupling reagents. The macrolactamization step proved to be difficult since only three of these hexapeptides could be cyclized. Two of these peptides were the linear precursors of the same cyclic hexapeptide, cyclo(Pro-Aib-Gly-Aib-AibPhe) (1). Surprisingly, they gave 1 in almost the same yield. Thus, 1 was obtained in 35% yield upon ring closure at the Phe/Pro site using DEPBT as the coupling reagent, whereas the cyclization at the Aib/Phe site led to 1 in 28 and 34% yield by using PyAOP and DEPC, respectively. Another cyclic hexapeptide, cyclo(GlyAib-Pro-Gly-Aib-Aib) (2) was prepared in 34% yield when DEPC was used in the cyclization step. The solid-state conformation of 1 was established by X-ray crystallography.3

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“…For this purpose, a wide variety of physical/chemical methods are employed. For example, the three-dimensional arrangement of critical side chain groups and backbone conformations can be analyzed via NMR spectroscopy [44,45], X-ray crystallography [46], circular dichroism measurements [47], and computational methods [48]. The next step is to find a suitable non-peptide scaffold which can impart the same 3D topographic structural features as the peptide based on conformational analysis, computational chemistry and 3D modeling.…”

Section: General Considerations For the Design Of Hmc3r Selective Agomentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Ligands Selective for the Melanocortin-3 Receptor

Hruby¹,

Cai²,

Cain³

et al. 2007

curr top med chem

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The processed products of the proopiomelanocortin gene (ACTH, α-MSH, β-MSH, γ-MSH, etc.) interact with five melanocortin receptors, the MC1R, MC2R, MC3R, MC4R, and MC5R to modulate and control many important biological functions crucial for good health both peripherally (as hormones) and centrally (as neurotransmitters). Pivotal biological functions include pigmentation, adrenal function, response to stress, fear/flight, energy homeostasis, feeding behavior, sexual function and motivation, pain, immune response, and many others, and are believed to be involved in many disease states including pigmentary disorders, adrenal disorders, obesity, anorexia, prolonged and neuropathic pain, inflammatory response, etc. The roeianocortin-3 receptor (MC3R) is found primarily in the brain and spinal cord and also in the periphery, and its biological functions are still not well understood. Here we review some of the biological functions attributed to the MC3R, and then examine in more detail efforts to design and synthesize ligands that are potent and selective for the MC3R, which might help resolve the many questions still remaining about its function. Though some progress has been made, there is still much to be done in this critical area.

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Crystal structures of peptides and modified peptides

Cited by 81 publications

References 231 publications

A designed beta-hairpin peptide in crystals.

A designed beta-hairpin peptide in crystals.

Synthesis of Cyclohexapeptides Containing Pro and Aib Residues.

Design, Synthesis and Biological Evaluation of Ligands Selective for the Melanocortin-3 Receptor

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