Human factor Xa bound amidine inhibitor conformation by double rotational-echo double resonance nuclear magnetic resonance and molecular dynamics simulations |
| |
Authors: | McDowell Lynda M McCarrick Margaret A Studelska Daniel R O'Connor Robert D Light David R Guilford William J Arnaiz Damian Adler Marc Dallas Jerry L Poliks Barbara Schaefer Jacob |
| |
Affiliation: | Department of Chemistry, Washington University, One Brookings Drive, St. Louis, Missouri 63130, USA. mcdowell@wuchem.wustl.edu |
| |
Abstract: | Double rotational-echo double resonance (double REDOR) NMR was used to investigate the conformation of a (13)C-, (15)N-, and (19)F-labeled inhibitor (Berlex Biosciences compound no. ZK-806299) bound to human factor Xa. Conformationally dependent carbon-fluorine dipolar couplings were measured by (13)C[(19)F] REDOR. Natural abundance carbon signals in the full-echo spectra were removed by (13)C[(15)N] REDOR. Major and minor binding modes were suggested by the NMR data, but only the former had adequate signal to noise for distance determinations. Molecular dynamics simulations restrained by double-REDOR-determined intramolecular (13)C-(19)F distances revealed two models for the dominant binding mode that are consistent with the NMR data. We conclude that ZK-806299 binds similarly to both FXa. Moreover, it appears to bind to FXa in a fashion previously demonstrated for ZK-807834, a more selective FXa inhibitor. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|