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Conformational Investigations on Analogs of Inflammation Response Inducing Chemotactic Tri-peptide, fMLP

Rathore, Ravindranath Singh (2005) Conformational Investigations on Analogs of Inflammation Response Inducing Chemotactic Tri-peptide, fMLP. In: Peptide Science .

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Abstract

Conformations of three analogs of for-L-Met-L-Leu-L-Phe-OH (fMLP), which initiates inflammatory response by interaction with formyl peptide receptor (FPR-1), have been investigated by the application of X-ray crystallographic technique. The investigated analogs of fMLP peptides are: for-L-Met-1-Amino-1-cyclooctane-carbonyl $({Ac}_{8}c)-L-Phe-OMe$ (1); for-L-Met-L-Leu-L-p-iodo-Phe-OH (2); and for-L-Met-Di-n-propylglycyl(Dpg)-L-Phe-OMe (3). Peptide backbone in 1 and 3 is constrained at position-2 of fMLP by the introduction of $C^{\alpha,\alpha}$-di-substituted glycines. In peptide 2, Phe-OMe is substituted by p-iodo- Phe-OH. Crystal structures reveal an over-all folded conformation adopted by 1 and 2. The former is folded in type-II \beta-turn, which is stabilized by an intramolecular 1 \leftarrow 4(formyl) C=O...H-N (Phe) hydrogen bond, whereas the latter is folded in an open-turn without any intramolecular hydrogen bond. On the other hand, peptide 3 has an extended conformation and two different molecules (3a, 3b) in a crystallographic asymmetric unit form an antiparallel \beta -sheet like structure. In 1 and 3, residues ${Ac}_{8}c$ and Dpg adopt left-handed helical and fully-extended $({C}_5)$ conformations, respectively. Cyclooctane ring in ${Ac}_{8}c$ acquires boat-chair conformation. Crystal packing of 1 is characterized by the association of aliphatic-aromatic rings via C-H..\pi interaction. In the crystal of 2, contrary to the usual observations, peptides are interlinked via networks of head-to-tail hydrogen bond and \pi-\pi interactions, which are generally observed to be mutually exclusive. The structure-function mechanism of ligand-receptor interaction is discussed.

Item Type: Journal Article
Additional Information: The copyright belongs to Wiley Periodicals, Inc. This is an online publication, ahead of print.
Keywords: fMLP/fMLF analogs;Formyl Peptide Receptor;chemotaxis;inflammation;aromatic interactions;crystal structures;GPCR;X-ray crystallography
Department/Centre: Division of Physical & Mathematical Sciences > Physics
Date Deposited: 09 Sep 2005
Last Modified: 19 Sep 2010 04:20
URI: http://eprints.iisc.ernet.in/id/eprint/3624

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