Insulation of cross-talk between signalingpathways-inspiration for innovative drug design
10.3969/j.issn.1001-1978.2017.07.004
- VernacularTitle:交叉对话信号的分子绝缘——对创新药物设计的思考
- Author:
Li TAO
;
Feng JIN
;
Haibo WANG
;
Yayun QIAN
;
Yun SUN
;
Yin LU
;
Yanqing LIU
- Keywords:
signaling transduction;
signaling cross-talk;
signaling insulation;
targetability;
drug accessibility;
protein dynamics;
drug design
- From:
Chinese Pharmacological Bulletin
2017;33(7):900-904
- CountryChina
- Language:Chinese
-
Abstract:
Cross-talk of intracellular signaling pathways that share common components (hubs) is organized in form of a bow-tie network topology.Signaling cross-talk is functionally pleiotropic for target genes regulation, resulting in functional redundancy, synergism and antagonism, which should be precisely controlled to prevent signaling 'leaking' or 'spillover'.Thus, the biological system has evolved multiple insulating mechanisms to achieve stimulus-specific response that maintains intracellular homeostasis.The insulation mechanism of signaling cross-talk suggests: (1) the functional duality of cross-talk molecules that determine cell fate requires selectively targeting dysregulated cross-talk molecules while protecting the normal ones from off-target or unintended effects, and we propose them as the targetable cross-talk molecules;(2) cross-talk molecules are usually carried on the macromolecular complex as their functional platforms, thus the structural plasticity of conformational changes at the interaction surface of cross-talk molecules asks for intensive work on the relationship study between drug binding and biological activity, which we propose as the accessible cross-talk molecules.Therefore, signaling cross-talk and its insulation mechanism play instructive leading roles in resolving the bottlenecks of current drug R&D and improve the clinical outcome.
