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Illkirch-Graffenstaden, France

Vivat Hannah V.,NovAliX Structural Biology | Atmanene C.,University of Strasbourg | Zeyer D.,NovAliX Structural Biology | Van Dorsselaer A.,University of Strasbourg | Sanglier-Cianferani S.,University of Strasbourg
Future Medicinal Chemistry | Year: 2010

The success of early drug-discovery programs depends on the adequate combination of complementary and orthogonal technologies allowing hit/lead compounds to be optimized and improve therapeutic activity. Among the available biophysical methods, native MS recently emerged as an efficient method for compound-binding screening. Native MS is a highly sensitive and accurate screening technique. This review provides a description of the general approach and an overview of the possible characterization of ligand-binding properties. How native MS supports structure- and fragment-based drug research will also be discussed, with examples from the literature and internal developments. Native MS shows strong potential for in-depth characterization of ligand-binding properties. It is also a reliable screening technique in drug-discovery processes. © 2010 Future Science Ltd. Source


Atmanene C.,NovAliX Structural Biology | Petiot-Becard S.,University of Strasbourg | Petiot-Becard S.,French National Center for Scientific Research | Zeyer D.,NovAliX Structural Biology | And 5 more authors.
Analytical Chemistry | Year: 2012

Evidencing subtle conformational transitions in proteins occurring upon small modulator binding usually requires atomic resolution techniques (X-ray crystallography or NMR). Recently, hyphenation of ion mobility and mass spectrometry (IM-MS) has greatly enlarged the potentials for biomolecular assembly structural characterization. Using the well 3D-characterized Bcl-xL/ABT-737 protein model, we explored in the present report whether IM-MS can be used to differentiate close conformers and monitor collision cross section (CCS) differences correlating with ligand-induced conformational changes. Because comparing CCS derived from IM-MS data with 3D-computed CCS is critical for thorough data interpretation, discussing pitfalls related to protein construct similarity and missing sequence sections in PDB files was of primary importance to avoid misinterpretation. The methodic exploration of instrument parameters showed enhanced IM separation of Bcl-xL conformers by combining high wave heights and velocities with low helium and nitrogen flow rates while keeping a high He/N2 flow rate ratio (>3). The robustness of CCS measurements was eventually improved with a modified IM calibration method providing constant CCS values regardless of instrument settings. Altogether, optimized IM-MS settings allowed a 0.4 nm2 increase (i.e., 2%) of Bcl-xL CCS to be evidenced upon ABT-737 binding. © 2012 American Chemical Society. Source

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