Determination of ligand binding modes in weak protein–ligand complexes using sparse NMR data

Mohanty, Biswaranjan, Williams, Martin L., Doak, Bradley C., Vazirani, Mansha, Ilyichova, Olga, Wang, Geqing, Bermel, Wolfgang, Simpson, Jamie S., Chalmers, David K., King, Glenn F., Mobli, Mehdi and Scanlon, Martin J. (2016) Determination of ligand binding modes in weak protein–ligand complexes using sparse NMR data. Journal of Biomolecular NMR, 1-14. doi:10.1007/s10858-016-0067-4

Author Mohanty, Biswaranjan
Williams, Martin L.
Doak, Bradley C.
Vazirani, Mansha
Ilyichova, Olga
Wang, Geqing
Bermel, Wolfgang
Simpson, Jamie S.
Chalmers, David K.
King, Glenn F.
Mobli, Mehdi
Scanlon, Martin J.
Title Determination of ligand binding modes in weak protein–ligand complexes using sparse NMR data
Journal name Journal of Biomolecular NMR   Check publisher's open access policy
ISSN 1573-5001
Publication date 2016-10-24
Sub-type Article (original research)
DOI 10.1007/s10858-016-0067-4
Open Access Status Not yet assessed
Start page 1
End page 14
Total pages 14
Place of publication Dordrecht, Netherlands
Publisher Springer Netherlands
Language eng
Formatted abstract
We describe a general approach to determine the binding pose of small molecules in weakly bound protein–ligand complexes by deriving distance constraints between the ligand and methyl groups from all methyl-containing residues of the protein. We demonstrate that using a single sample, which can be prepared without the use of expensive precursors, it is possible to generate high-resolution data rapidly and obtain the resonance assignments of Ile, Leu, Val, Ala and Thr methyl groups using triple resonance scalar correlation data. The same sample may be used to obtain Met εCH3 assignments using NOESY-based methods, although the superior sensitivity of NOESY using [U-13C,15N]-labeled protein makes the use of this second sample more efficient. We describe a structural model for a weakly binding ligand bound to its target protein, DsbA, derived from intermolecular methyl-to-ligand nuclear Overhauser enhancements, and demonstrate that the ability to assign all methyl resonances in the spectrum is essential to derive an accurate model of the structure. Once the methyl assignments have been obtained, this approach provides a rapid means to generate structural models for weakly bound protein–ligand complexes. Such weak complexes are often found at the beginning of programs of fragment based drug design and can be challenging to characterize using X-ray crystallography.
Keyword High ambiguity driven biomolecular docking (HADDOCK)
Non-uniform sampling (NUS)
Protein–ligand complexes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
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