Genome-wide analysis of LXXLL-mediated DAX1/SHP–nuclear receptor interaction network and rational design of stapled LXXLL-based peptides to target the specific network profile
| Autor: | Haihong Qian, Ping He, Wei Wu, Fenglin Lv |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Protein Conformation Amino Acid Motifs Quantitative Structure-Activity Relationship Receptors Cytoplasmic and Nuclear Peptide binding Peptide 02 engineering and technology Computational biology Biochemistry 03 medical and health sciences Structural Biology Interaction network Protein Interaction Mapping Cluster Analysis Humans Protein Interaction Domains and Motifs Amino Acid Sequence Protein Interaction Maps Receptor Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Binding Sites DAX-1 Orphan Nuclear Receptor Chemistry Rational design General Medicine 021001 nanoscience & nanotechnology Nuclear receptor Drug Design Human genome DAX1 Peptides 0210 nano-technology Genome-Wide Association Study Protein Binding |
| Zdroj: | International Journal of Biological Macromolecules. 129:13-22 |
| ISSN: | 0141-8130 |
| Popis: | The atypical orphan receptors DAX1 and SHP constitute the NR0B subgroup of human nuclear receptor (hNR) family; they play key roles in metabolism, reproduction, nutrition and steroidogenesis, and are involved in the pathogenesis of a variety of diseases such as cancer and adrenal hypoplasia. The two receptors lack the classical DNA-binding domain and act as the corepressors of other hNRs. The DAX1 and SHP contains three and two conserved LXXLL motifs, respectively, which can be recognized and bound by the activation function-2 (AF-2) domain of hNR proteins in agonist conformation. Here, we attempt to explore the systematic interaction profile between the five DAX1/SHP LXXLL motifs and all the 48 hNR AF-2 domains found in the human genome, to analyze the binding affinity and specificity of these motifs towards the complete domain array, and to design LXXLL-based, hydrocarbon-stapled peptides that can target the specific interaction profile for each motif. A weighted source-target network from motifs to domains is created based on the modeled domain-motif complex structures and calculated binding potencies, from which the specific interaction profile of each motif against the whole hNR array is depicted and clustered to measure the binding similarity and relationship among these motifs. Dynamics simulations reveal that the LXXLL-based peptides are highly flexible in free unbound state, thus unfavorable to be recognized and bound by AF-2 domains. Hydrocarbon-stapling technique is employed to help the constraint of these unstructured peptides to active helical conformation, thus largely improving their binding affinity to the hNR array. The hydrocarbon bridge is designed to point out of the domain's active pocket, which would not disrupt the direct interaction between the domain and peptide. Energetic decomposition imparts that the stapling has only a very modest influence on the interaction enthalpy and desolvation effect of domain-peptide binding, but can substantially reduce entropy penalty upon the binding. For a peptide ligand, the entropic reduction can be roughly regarded as a constant, which only improves (absolute) peptide binding affinity towards the whole domain array, but does not alter (relative) peptide binding specificity over different domains in the array. Overall, the stapled peptides can be considered as potent competitors to selectively target the specific interaction networks mediated by their parent LXXLL motifs in DAX1 and SHP proteins. |
| Databáze: | OpenAIRE |
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