A crystal structure determination for Tyr-D-Nle-Gly-Phe-NleS [NleS = MeCH2CH2CH2CH(NH2)SO3H]: an active synthetic enkephalin analogue

Stezowski, John J.; Eckle, Emil; Bajusz, S.

doi:10.1039/c39850000681

Cited by 16 publications

(6 citation statements)

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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.…”

Section: Introductionmentioning

confidence: 99%

A designed beta-hairpin peptide in crystals.

Karle

Awasthi

Balaram

1996

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

169

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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Section: Introductionmentioning

confidence: 99%

A designed beta-hairpin peptide in crystals.

Karle

Awasthi

Balaram

1996

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

169

123

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“…The torsion angles listed in Table 2 show that the backbone conformation of RTI02 closely resembles the double [3-bend Leu-enkephalin structure observed by Aubry [5]. However, it is markedly different from the fully extended or single [3-bend solid state conformations found to date for acyclic endogenous enkephalins and their analogs [3,4,8,9,[25][26][27][28]. The most noticeable difference between these structures, related to important pharmacophoric features, is the approach between the aromatic rings.…”

Section: Fig 2 Hydrogen Bonding In Rti02 Only the Peptide Backbonementioning

confidence: 86%

“…The structures were solved by direct methods with the aid of the program SHELX86 [19] and refined on F'; values using the full-matrix leastsquares program SHELXL-93 [20] on the full set of independent data, as described elsewhere [8]. In SHELXL-93 the origin is fixed by using polar axis restraints [21].…”

Section: X-ray Crystallographymentioning

confidence: 99%

“…Of all the X-ray structures reported on the endogenous enkephalins or their analogs, only Leuenkephalin has shown this double [3-bend conformation [5]. Other structures exhibit either fully extended or single type I' f3-bend conformations [3,4,8,9,[25][26][27][28]. In RTI02 both the N-and Ctermini have been blocked, as has the hydroxyl group on Tyr ~, leaving only the H atoms on N2, N3 and the methanol OH available for additional hydrogen bonding.…”

Section: (Nn-diallyl-( O-t-butyl)-tyr-aib-aib-methyl Ester)mentioning

confidence: 99%

“…In fact, the deltorphins, a naturally occurring family of opioid peptides having a Dresidue in position 2, have shown high affinity and selectivity for the fi-receptor site [7]. The presence of a D-residue in position 2 does appear to impose a conformational preference for a folded rather than an extended peptide backbone, as has been found in three X-ray structures of this type of enkephalin analog: Tyr-D-Nle-Gly-Phe-NleS [8], Tyr-D-Thr-Gly-Phe-Leu-Thr-OH (DTLET, Ref. 9) and Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE, Ref.…”

Section: Introductionmentioning

confidence: 99%

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X-ray structures of the ? opioid antagonist TIPP and a protected derivative of the ? opioid antagonist ICI 174,864

Flippen‐Anderson¹,

George²,

Deschamps³

et al. 1994

Lett Pept Sci

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The solid state structures of two synthetic opioid peptides have been determined by X-ray single crystal analysis. The first X-ray structure is that of N,N-diallyl-(O-t-butyl)-Tyr-Aib-Aib-Phe-Leu-OMe (RTI02), a protected derivative of the 5-receptor selective antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH. ICI 174,864 is one of a series of rationally designed Aib-substituted enkephalin analogs which have shown site-specific antagonist properties. The second compound, the tetrapeptide Tyr-Tic-Phe-Phe-OH (TIPP), is one of a family of linear peptides containing the conformationally restricted Tic residue (tetrahydroisoquinoline-3-carboxylic acid). TIPP exhibits high affinity, selectivity and antagonism for the 8-receptor, Crystals of both peptides were obtained by slow evaporation and found to be monoclinic in space group P2j. Unit cell dimensions for RTI02 were: a = 13.619(4)/~, b = 12.467(3)/~, c = 13.750(4)/~, [3 = 96.03(4) ° and V = 2322(1) A 3. The asymmetric unit contained one molecule of RTI02 and one molecule of methanol, giving a calculated density of 1.156 g cm -3. Unit cell dimensions for TIPP were: a = 8.879(5) ,~, b = 20.146(8) ,~, c = 12.710(6) ,~, [3 = 107.89(2) ° and V = 2164(2) ,~3 The asymmetric unit contained one molecule of TIPP and three molecules of acetic acid, giving a calculated density of 1.251 g cm -3. The RTI02 backbone has a double [3-bend, stabilized by two intramolecular hydrogen bonds. The TIPP backbone is also folded, but with only a single bend, stabilized by one intramolecular hydrogen bond and several hydrogen bonds to solvent molecules. Both compounds contain aromatic rings in close vicinity (4-6/~).

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Structural studies of opioid peptides: A review of recent progress in x-ray diffraction studies

Deschamps¹,

George²,

Flippen‐Anderson³

1996

Biopolymers

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The solid state structures of many opioid peptide agonists have been elucidated by x-ray diffraction analysis. Recently, the first structure of an opioid peptide antagonist has been determined. Theoretically, linear peptides can have many different backbone conformations, yet early x-ray studies (1983-1987) on enkephalin and its analogues showed only two different backbone conformations: extended and single beta-bend. In 1989 enkephalin was observed in a third conformation, a double beta-bend. Since that time diffraction studies have been completed on the rationally designed linear opioid peptide agonists DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) and DADLE (D-Ala2,D-Leu5-enkephalin) as well as on several cyclic enkephalin analogues including DPDPE (Tyr-[D-Pen-Gly-Phe-D-Pen]) and JOM-13 (Tyr-[D-Cys-Phe-D-Pen]). The most recent review of the x-ray studies on this class of compounds was written in 1988. This paper will update that review to include the results of studies completed since that time.

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A crystal structure determination for Tyr-D-Nle-Gly-Phe-NleS [NleS = MeCH2CH2CH2CH(NH2)SO3H]: an active synthetic enkephalin analogue

Abstract: A crystal structure determination for Tyr-o-Nle-Gly-Phe-NIeS [NleS = MeCH2CH2CH2CH(NH2)S03H] provides t w o examples of a 2'-P-bend conformation for a biologically active, synthetic enkephalin analogue.

Cited by 16 publications

References 0 publications

A designed beta-hairpin peptide in crystals.

A designed beta-hairpin peptide in crystals.

X-ray structures of the ? opioid antagonist TIPP and a protected derivative of the ? opioid antagonist ICI 174,864

Structural studies of opioid peptides: A review of recent progress in x-ray diffraction studies

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