2. Academic Validation
  3. The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport

The ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport

  • FEBS Lett. 2024 Jun 17. doi: 10.1002/1873-3468.14955.
Yue Zhu 1 2,  Xiaoke Xing 2,  Fuxing Wang 3,  Luojun Chen 2,  Chunhui Zhong 3,  Xiting Lu 4,  Zhanwang Yu 4,  Yongbo Yang 5,  Yi Yao 2,  Qibin Song 2,  Suxia Han 1,  Zheng Liu 3,  Pingfeng Zhang 2
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, China.
  • 2 Cancer Center, Renmin Hospital of Wuhan University, China.
  • 3 Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, China.
  • 4 School of Applied Biology, Shenzhen Institute of Technology, China.
  • 5 School of Life Sciences, Central China Normal University, Wuhan, China.
PMID: 38886124 DOI: 10.1002/1873-3468.14955
Abstract

The multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward-open conformation with an ATP bound to degenerate NBD1. Additionally, we captured the structure with both ATP and substrate co-bound in the inward-open state. Our findings uncover the asymmetric ATP binding in ABCC4 and provide insights into substrate binding and transport mechanisms. ATP binding to NBD1 is parallel to substrate binding to ABCC4, and is a prerequisite for ATP-bound NBD2-induced global conformational changes. Our findings shed new light on targeting ABCC4 in combination with Anticancer therapy.

Keywords

ABCC4; MRP4; asymmetric ATP binding; degenerate NBD1; methotrexate.

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