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Structure-based rational design of self-inhibitory peptides to disrupt the intermolecular interaction between the troponin subunits C and I in neuropathic pain.
- Source :
-
Bioorganic Chemistry . Aug2017, Vol. 73, p10-15. 6p. - Publication Year :
- 2017
-
Abstract
- The troponin (Tn) is a ternary complex consisting of three subunits TnC, TnI and TnT; molecular disruption of the Tn complex has been recognized as an attractive strategy against neuropathic pain. Here, a self-inhibitory peptide is stripped from the switch region of TnI interaction interface with TnC, which is considered as a lead molecular entity and then used to generate potential peptide disruptors of TnC–TnI interaction based on a rational molecular design protocol. The region is a helical peptide segment capped by N- and C-terminal disorders. Molecular dynamics simulation and binding free energy analysis suggests that the switch peptide can interact with TnC in a structurally and energetically independent manner. Terminal truncation of the peptide results in a number of potent TnC binders with considerably simplified structure and moderately decreased activity relative to the native switch. We also employ fluorescence polarization assays to substantiate the computational findings; it is found that the rationally designed peptides exhibit moderate or high affinity to TnC with dissociation constants K D at micromolar level. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00452068
- Volume :
- 73
- Database :
- Academic Search Index
- Journal :
- Bioorganic Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 124187343
- Full Text :
- https://doi.org/10.1016/j.bioorg.2017.05.004