Elucidation of a nutlin-derivative—HDM2 complex structure at the interaction site by NMR molecular replacement: A straightforward derivation
- Author(s)
- Valerie Mertens, Marie Jose Abi Saad, Nicolas Coudevylle, Marielle Aulikki Wälti, Aaron Finke, May Marsh, Julien Orts
- Abstract
Protein—ligand complex structures are key in structure-based drug discovery, but their derivation largely relies on X-ray crystallography. While NMR is able to provide atomic resolution complex structures, traditional NMR structure calculation methods are too slow for drug discovery timelines. We recently developed the NMR molecular replacement (NMR2) method that substantially reduces the time needed to derive protein—ligand complex structures, mainly by bypassing the laborious protein sequential resonance assignment step. Here we show how we applied NMR2 to derive the structure of the protein HDM2 in complex with the small molecule caylin-1, an analog of nutlin, based on the HDM2—nutlin complex structure that was already derived by NMR2. This study illustrates how sparse information from a previous NMR2 structure elucidation can be employed to efficiently determine further protein-analog complex structures. We think NMR2 has the potential to become a major tool in structure-based drug discovery, especially when X-ray crystallography is difficult to implement.
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- Eidgenössische Technische Hochschule Zürich, Paul Scherrer Institute
- Journal
- Journal of Magnetic Resonance Open
- Volume
- 10-11
- ISSN
- 2666-4410
- DOI
- https://doi.org/10.1016/j.jmro.2022.100032
- Publication date
- 2022
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 106006 Biophysics, 106002 Biochemistry
- Keywords
- ASJC Scopus subject areas
- Electronic, Optical and Magnetic Materials, Analytical Chemistry, Radiology Nuclear Medicine and imaging, Spectroscopy
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/elucidation-of-a-nutlinderivativehdm2-complex-structure-at-the-interaction-site-by-nmr-molecular-replacement-a-straightforward-derivation(4fb33ebc-b761-4b61-bce4-8f0b21191576).html