A crystal molecular conformation of leucine‐enkephalin related to the morphine molecule

Aubry, A.; Birlirakis, Nicolas; Sakarellos‐Daitsiotis, Maria; Sakarellos, C.; Marraud, Michel

doi:10.1002/bip.360280106

Cited by 101 publications

(98 citation statements)

References 28 publications

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“…For analogues 20a-c and 21a-b with the D-and L-bicyclo moiety, extended structures were found at these two positions, also independent of the bridgehead stereochemistry. These findings rationalize the design and use of these bicyclic dipeptides in our study to mimic the different conformations reported [35][36][37][38][39][40] on Leu-enkephalin. However, it must be noted that the analogue (21c) with the same D-and L-bicyclo moiety gives a reverse turn structure instead of an extended structure.…”

Section: Conformational Studiessupporting

confidence: 81%

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Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Gu¹,

Ying²,

Min³

et al. 2005

Biopolymers

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show abstract

Section: Conformational Studiessupporting

confidence: 81%

“…In previous conformational studies [35][36][37][38][39][40] on this endogenous neuropeptide, both turn and extended conformations spanning residues 2-3 were reported. Depending on the configurations of the chiral centers in the bicyclic dipeptides, these dipeptides may be constrained to different conformations.…”

Section: Conformational Studiesmentioning

confidence: 99%

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Gu¹,

Ying²,

Min³

et al. 2005

Biopolymers

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“…A wide range of conformations has been found for enkephalin peptides in crystal (39), in Me 2 SO solution, or bound to membranes (for review, see Ref. 40), most of them involving ␤ turn and ␥ turn conformations, but no helical conformation has yet been described.…”

Section: Discussionmentioning

confidence: 99%

Solution Conformation of the Synthetic Bovine Proenkephalin-A209–237 by 1H NMR Spectroscopy

Kieffer¹,

Dillmann²,

Lefèvre³

et al. 1998

Journal of Biological Chemistry

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Proenkephalin-A has been described to generate enkephalins, opoid peptides, and several derived peptides, which display various biological effects, including antinociception and immunological enhancement. Recently, we have isolated from bovine chromaffin granules a new antibacterial peptide, named enkelytin, which corresponds to the bisphosphorylated form of PEAP 209 -237 (Goumon, Y., Strub, J. M., Moniatte, M., Nullans, G., Poteur, L., Hubert, P., Van Dorsselaer, A., Aunis, D., and Metz-Boutigue, M. H. (1996) Eur. J. Biochem. 235, 516 -525). In this paper, the three-dimensional solution structure of synthetic PEAP 209 -237 was investigated by NMR. These studies indicate that this peptide, which is unstructured in water, folds into an ␣-helical structure in trifluoroethanol/water (1/1). NMR data revealed two possible three-dimensional models of PEAP 209 -237 . In both models, the proline residue Pro-227 induces a 90°h inge between two ␣-helical segments (Ser-215 to Ser-221 and Glu-228 to Arg-232) leading to an overall Lshaped structure for the molecule. The negative charge of PEAP 209 -237 and the low amphipathy of the two ␣-helical segments imply new mechanisms to explain the antibacterial activity of enkelytin.Proenkephalin-A (PEA), 1 the precursor of enkephalins (1), and several derived peptides (PEAP) (2, 3) have been described in neural, neuroendocrine, and immune cells (4). This precursor to the opioid pentapeptides is highly conserved from invertebrates (leech, mytilus) (5), Xenopus (6) to humans (7). Because relatively large amounts of enkephalins and enkephalincontaining peptides were present in adrenal medullary chromaffin granules, these organelles have been shown to represent an excellent model to study the intragranular processing of PEA (for review, see Ref. 8). Proteolytic degradation of PEA in adrenal medulla appears to start at the COOH-terminal region with the removal of peptide B, PEAP 209 -239 (9). Immunoreactive forms of peptide B can be found in various regions of brain and circulating in plasma (10). From bovine adrenal medulla, four peptide B variants were isolated corresponding to the addition of one, two, or three phosphate groups to each peptide chain (11, 12), the phosphorylation sites being clustered together at positions Ser-215, Ser-221, and Ser-223.Among the complex mixture of intragranular matrix components, we have identified enkelytin, an antibacterial peptide corresponding to the bisphosphorylated PEAP 209 -237 , which is included in peptide B (13). More recently, a new antibacterial peptide, exhibiting 98% sequence identity with bovine enkelytin, has been identified as derived from leech and mytilus PEA (14).2 In both mammals and invertebrates, opioid peptides stimulate immune cells, triggering chemotaxis as well as secretion of cytokines (4).Enkelytin is active at a concentration around the micromolar range against several Gram-positive bacteria including Staphylococcus aureus, but it is unable to inhibit the Gram-negative bacteria growth (13, 16). Furthermore, enkelytin has...

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“…3 The lack of specifi city may be related to the large number of conformations available to the peptides. However, in the crystalline state Leu-enkephalin has been shown to exist in only 3 conformations ( Figure 1 ), extended, 4 single ␤ -bend, 5 and double ␤ -bend, 6 while Met-enkephalin 7 has only been seen in an extended conformation. Thus the lack of specifi city may be related to differential binding of these conformers at the various opioid receptors.…”

Section: Conformation and Biologic Activitymentioning

confidence: 99%

The Role of Crystallography in Drug Design

Deschamps¹

2008

Drug Addiction

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Structure and function are intimately related. Nowhere is this more important than the area of bioactive molecules. It has been shown that the enantioselectivity of an enzyme is directly related to its chirality. X-ray crystallography is the only method for determining the " absolute " confi guration of a molecule and is the most comprehensive technique available to determine the structure of any molecule at atomic resolution. Results from crystallographic studies provide unambiguous, accurate, and reliable 3-dimensional structural parameters, which are prerequisites for rational drug design and structure-based functional studies.

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A crystal molecular conformation of leucine‐enkephalin related to the morphine molecule

Cited by 101 publications

References 28 publications

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Solution Conformation of the Synthetic Bovine Proenkephalin-A209–237 by 1H NMR Spectroscopy

The Role of Crystallography in Drug Design

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A crystal molecular conformation of leucine‐enkephalin related to the morphine molecule

Cited by 101 publications

References 28 publications

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

Solution Conformation of the Synthetic Bovine Proenkephalin-A209–237 by 1H NMR Spectroscopy

The Role of Crystallography in Drug Design

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Product

Resources

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Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues