6A71

Crystal Structure of Human ATP7B and TM Complex

Summary for 6A71

• Entry DOI: 10.2210/pdb6a71/pdb
• Descriptor: ATP7B protein, DI(HYDROXYETHYL)ETHER, GLYCEROL, ... (6 entities in total)
• Functional Keywords: copper transporter protein, metal transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 15341.16

Authors

Chen, W.B. (deposition date: 2018-06-30, release date: 2019-04-03, Last modification date: 2023-11-22)

Primary citation

Fang, T.,Chen, W.,Sheng, Y.,Yuan, S.,Tang, Q.,Li, G.,Huang, G.,Su, J.,Zhang, X.,Zang, J.,Liu, Y.
Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein.
Nat Commun, 10:186-186, 2019

PubMed Abstract: Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson's disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged MoSO cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.

PubMed: 30643139
DOI: 10.1038/s41467-018-08102-z

Experimental method

X-RAY DIFFRACTION (1.6 Å)