2heo

File:2heo.gif

spinqualitylabelsall models 2heo, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

General Structure-Based Approach to the Design of Protein Ligands: Application to the Design of Kv1.2 Potassium Channel Blockers.

OverviewOverview

We have developed a structure-based approach to the design of protein, ligands. This approach is based on the transfer of a functional binding, motif of amino acids, often referred as to the "hot spot", on a host, protein able to reproduce the functional topology of these residues. The, scaffolds were identified by a systematic in silico search in the Protein, Data Bank for proteins possessing a group of residues in a topology, similar to that adopted by the functional motif in a reference ligand of, known 3D structure. In contrast to previously reported studies, this, search is independent of the particular secondary structure supporting the, functional motif. To take into account the global properties of the host, protein, two additional criteria were taken into account in the selection, process: (1) Only those scaffolds sterically compatible with the, positioning of the functional motif as observed in a reference complex, model were retained. (2) Host proteins displaying electrostatic, potentials, in the region of the transferred functional motif, similar to, that of the reference ligand were selected. This approach was applied to, the development of protein ligands of the Kv1.2 channel using BgK, a small, protein isolated from the sea anemone Bunodosoma granulifera, as the, reference ligand. Four proteins obtained by this approach were produced, for experimental evaluation. The X-ray structure of one of these proteins, was determined to check for similarity of the transferred functional motif, with the structure it adopts in the reference ligand. Three of these, protein ligands bind the Kv1.2 channel with inhibition constants of 0.5, 1.5, and 1.6 microM. Several mutants of these designed protein ligands, gave binding results consistent with the presumed binding mode. These, results show that protein ligands can be designed by transferring a, binding motif on a protein host selected to reproduce the functional, topology of this motif, irrespective to the secondary structure supporting, the functional motif, if the host protein possesses steric and, electrostatic properties compatible with the binding to the target. This, result opens the way to the design of protein ligands by taking advantage, of the considerable structural repertoire of the Protein Data Bank.

About this StructureAbout this Structure

2HEO is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.

ReferenceReference

Structure-based secondary structure-independent approach to design protein ligands: Application to the design of Kv1.2 potassium channel blockers., Magis C, Gasparini D, Lecoq A, Le Du MH, Stura E, Charbonnier JB, Mourier G, Boulain JC, Pardo L, Caruana A, Joly A, Lefranc M, Masella M, Menez A, Cuniasse P, J Am Chem Soc. 2006 Dec 20;128(50):16190-205. PMID:17165772

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