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An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe

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Title: An NMR strategy for fragment-based ligand screening utilizing a paramagnetic lanthanide probe
Authors: Saio, Tomohide Browse this author
Ogura, Kenji Browse this author
Shimizu, Kazumi Browse this author
Yokochi, Masashi Browse this author
Burke, Terrence R., Jr. Browse this author
Inagaki, Fuyuhiko Browse this author →KAKEN DB
Keywords: Ligand screening
Fragment-based drug design (FBDD)
Protein-ligand structure
Lanthanide-binding peptide tag (LBT)
Paramagnetic relaxation enhancement (PRE)
Pseudo-contact shift (PCS)
Issue Date: Nov-2011
Publisher: Springer Netherlands
Journal Title: Journal of Biomolecular NMR
Volume: 51
Issue: 3
Start Page: 395
End Page: 408
Publisher DOI: 10.1007/s10858-011-9566-5
Abstract: A nuclear magnetic resonance-based ligand screening strategy utilizing a paramagnetic lanthanide probe is presented. By fixing a paramagnetic lanthanide ion to a target protein, a pseudo-contact shift (PCS) and a paramagnetic relaxation enhancement (PRE) can be observed for both the target protein and its bound ligand. Based on PRE and PCS information, the bound ligand is then screened from the compound library and the structure of the ligand-protein complex is determined. PRE is an isotropic paramagnetic effect observed within 30Å from the lanthanide ion, and is utilized for the ligand screening in the present study. PCS is an anisotropic paramagnetic effect providing long-range (∼40Å) distance and angular information on the observed nuclei relative to the paramagnetic lanthanide ion, and utilized for the structure determination of the ligand-protein complex. Since a two-point anchored lanthanide-binding peptide tag is utilized for fixing the lanthanide ion to the target protein, this screening method can be generally applied to non-metal-binding proteins. The usefulness of this strategy was demonstrated in the case of the growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain and its low- and high-affinity ligands.
Type: article
Appears in Collections:生命科学院・先端生命科学研究院 (Graduate School of Life Science / Faculty of Advanced Life Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 稲垣 冬彦

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