Journal
CHEMBIOCHEM
Volume 21, Issue 21, Pages 3087-3095Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202000348
Keywords
fuzzy complexes; molecular dynamics simulations; NMR structures; p53; protein folding
Funding
- National Research, Development and Innovation Office [NKFIH-1157-8/2019-DT]
- National Research Development and Innovation Fund of Hungary [2018-1.2.1-NKP-2018-00005, 2018-1.2.1-NKP]
- NKFI grant [K124900, K116305]
- MedInProt program
- Projekt DEAL
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Conformationally flexible protein complexes represent a major challenge for structural and dynamical studies. We present herein a method based on a hybrid NMR/MD approach to characterize the complex formed between the disordered p53TAD(1-60)and the metastasis-associated S100A4. Disorder-to-order transitions of both TAD1 and TAD2 subdomains upon interaction is detected. Still, p53TAD(1-60)remains highly flexible in the bound form, with residues L26, M40, and W53 being anchored to identical hydrophobic pockets of the S100A4 monomer chains. In the resulting fuzzy complex, the clamp-like binding of p53TAD(1-60)relies on specific hydrophobic anchors and on the existence of extended flexible segments. Our results demonstrate that structural and dynamical NMR parameters (cumulative Delta delta, SSP, temperature coefficients, relaxation time, hetNOE) combined with MD simulations can be used to build a structural model even if, due to high flexibility, the classical solution structure calculation is not possible.
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