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TitleThe ATP-bound inward-open conformation of ABCC4 reveals asymmetric ATP binding for substrate transport.
Journal, issue, pagesFEBS Lett, Year 2024
Publish dateJun 17, 2024
AuthorsYue Zhu / Xiaoke Xing / Fuxing Wang / Luojun Chen / Chunhui Zhong / Xiting Lu / Zhanwang Yu / Yongbo Yang / Yi Yao / Qibin Song / Suxia Han / Zheng Liu / Pingfeng Zhang /
PubMed AbstractThe multidrug resistance-associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor ...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.
External linksFEBS Lett / PubMed:38886124
MethodsEM (single particle)
Resolution3.02 - 3.05 Å
Structure data

38533

8xol

EMDB-38533, PDB-8xol:
Cryo-EM structure of human ABCC4 with ANP bound in NBD1
Method: EM (single particle) / Resolution: 3.02 Å

38534

8xom

EMDB-38534, PDB-8xom:
Cryo-EM structure of human ABCC4 in complex with ANP-bound in NBD1 and METHOTREXATE
Method: EM (single particle) / Resolution: 3.05 Å

Chemicals

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-DU0:
2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol

ChemComp-PLM:
PALMITIC ACID

ChemComp-MG:
Unknown entry

ChemComp-MTX:
METHOTREXATE / chemotherapy*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / ABC transporter MRP

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