This study investigates the effect of protein properties on the nanomaterial-protein interaction and elucidates the molecular mechanisms underlying the targeted inhibition of polo-like kinase (PLK1) by black phosphorus nanomaterials (BPNMs). The specific targeting inhibition is attributed to the intrinsic properties of both the PLK1 protein and the BPNMs. Notably, BPNMs specifically bind to PLK1, while exhibiting no binding affinity to homologous proteins within PLK family. BPNMs effectively suppress PLK1 activity by binding to critical amino acid residues in both the kinase domain and polo-box domain. Specifically, BPNMs target to the residues S49, known as a phosphorylation site, as well as to the residues Y203, D204, E206, and R207, which are all located within the activation loop of the kinase domain and critical for PLK1 activation. Additionally, R337 is situated in the D-box region, playing a vital role in PLK1 degradation, and is also specifically attached to BPNMs. By specifically targeting PLK1, BPNMs disrupt the normal cell cycle and present themselves as a potential candidate for targeted chemotherapeutic agents.
Abstract:
The intrinsic properties of black phosphorus (BP) nanomaterials (NMs) enable them for targeted binding to polo-like kinase 1 (PLK1), thus inhibiting its kinase activity. However, the mechanism and targeted binding sites underlying this interaction remain unclear. To elucidate the critical properties of PLK1 that facilitate its interaction with BPNMs, the binding ability of BPNMs was compared across PLK family proteins. Although BPNMs exhibited a weak binding affinity for PLK3, PLK1 demonstrated the most favorable physicochemical properties for its binding. Factors as surface charge, hydrophobicity, secondary and three-dimensional structures significantly affected the interaction of PLK family proteins to BPNMs. The binding affinity was primarily determined by amino acid residues at the binding interface, where arginine and proline played critical roles in mediating the interaction of BPNMs-PLK1. BPNMs inhibited PLK1 activation by binding to key residues of the kinase domain, including S49, Y203, D204, E206, and R207. In conclusion, this study elucidates the molecular basis of the specific interaction between BPNMs and PLK1, highlighting the pivotal role of the amino acid residues in NM-protein binding. This work demonstrates that NM-protein interactions are a mutual selection and driven by the physicochemical properties of both proteins and NMs.
Author list:
Fangfang Liu†, Zhong-Da Li†, Yanqiao Zeng†, Xiaofeng Wang, Yingnan Liu, Qi Li, Wenhe Luo, Xiaoman Suo, Yaqing Xu, Feng Yuan, Dan Zhang, Wuqiong Zhang, Shengyong Geng, Xue-Feng Yu, Guofang Zhang*, Yang Li*
How to cite:
F. Liu, Z.-D. Li, Y. Zeng, X. Wang, Y. Liu, Q. Li, W. Luo, X. Suo, Y. Xu, F. Yuan, D. Zhang, W. Zhang, S. Geng, X.-F. Yu, G. Zhang, Y. Li, Exploration 2025, 20240143.
https://doi.org/10.1002/EXP.20240143