Atomic resolution Protein Allostery from the multi-state Structure of a PDZ Domain

Ashkinadze, D.; Kadavath, H.; Chi, C. N.; Friedmann, M.; Strotz, D.; Kumari, P.; Minges, M.; Cadalbert, R.; KÖnigl, S.; Güntert, P.; Vogeli, B.; Riek, R.

doi:10.1101/2021.11.23.469649

bioRxiv · 10.1101/2021.11.23.469649

Atomic resolution Protein Allostery from the multi-state Structure of a PDZ Domain

Ashkinadze, D.·Kadavath, H.·Chi, C. N.·Friedmann, M.·Strotz, D.·Kumari, P.·Minges, M.·Cadalbert, R.·KÖnigl, S.·Güntert, P.·Vogeli, B.·Riek, R.

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Abstract

Recent methodological advances in solution NMR allow the determination of multi-state protein structures and provide insights into correlated motion at atomic resolution as demonstrated here for the well-studied PDZ2 domain of protein human tyrosine phosphatase 1E for which protein allostery was predicted. Two-state protein structures were calculated for both the free form and in complex with the RA-GEF2 peptide using the exact nuclear Overhauser effect (eNOE) method. In the apo protein states an allosteric conformational preselection step comprising almost 60% of the domain was detected with an "open" ligand welcoming state and a "closed" state that obstructs the binding site by the distance between the {beta}-sheet, -helix 2 and sidechains of residues Lys38 and Lys72. Observed apo-holo structural rearrangements of induced fit-type are in line with previously published evolution-based analysis covering ~25% of the domain with only a partial overlap with the protein allostery of the open form. These presented structural studies highlight the presence of a dedicated highly optimized dynamic interplay of the complexity of the PDZ2 domain owed by the structure-dynamics landscape.

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Ashkinadze, D., Kadavath, H., Chi, C. N., Friedmann, M., Strotz, D., Kumari, P., Minges, M., Cadalbert, R., KÖnigl, S., Güntert, P., Vogeli, B., Riek, R.. 2021-11-24. Atomic resolution Protein Allostery from the multi-state Structure of a PDZ Domain. https://doi.org/10.1101/2021.11.23.469649

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