Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states.
Journal, issue, pages	Nature, Vol. 563, Issue 7731, Page 426-430, Year 2018
Publish date	Nov 7, 2018
Authors	Ioannis Manolaridis / Scott M Jackson / Nicholas M I Taylor / Julia Kowal / Henning Stahlberg / Kaspar P Locher /
PubMed Abstract	ABCG2 is a transporter protein of the ATP-binding-cassette (ABC) family that is expressed in the plasma membrane in cells of various tissues and tissue barriers, including the blood-brain, blood- ...ABCG2 is a transporter protein of the ATP-binding-cassette (ABC) family that is expressed in the plasma membrane in cells of various tissues and tissue barriers, including the blood-brain, blood-testis and maternal-fetal barriers. Powered by ATP, it translocates endogenous substrates, affects the pharmacokinetics of many drugs and protects against a wide array of xenobiotics, including anti-cancer drugs. Previous studies have revealed the architecture of ABCG2 and the structural basis of its inhibition by small molecules and antibodies. However, the mechanisms of substrate recognition and ATP-driven transport are unknown. Here we present high-resolution cryo-electron microscopy (cryo-EM) structures of human ABCG2 in a substrate-bound pre-translocation state and an ATP-bound post-translocation state. For both structures, we used a mutant containing a glutamine replacing the catalytic glutamate (ABCG2), which resulted in reduced ATPase and transport rates and facilitated conformational trapping for structural studies. In the substrate-bound state, a single molecule of estrone-3-sulfate (ES) is bound in a central, hydrophobic and cytoplasm-facing cavity about halfway across the membrane. Only one molecule of ES can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains (NBDs), and a change in the relative orientation of the NBD subdomains. Mutagenesis and in vitro characterization of transport and ATPase activities demonstrate the roles of specific residues in substrate recognition, including a leucine residue that forms a 'plug' between the two cavities. Our results show how ABCG2 harnesses the energy of ATP binding to extrude ES and other substrates, and suggest that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors.
External links	Nature / PubMed:30405239 / PubMed Central
Methods	EM (single particle)
Resolution	3.09 - 3.58 Å
Structure data	0190 6hbu 6hzm EMDB-0190, PDB-6hbu: Cryo-EM structure of the ABCG2 E211Q mutant bound to ATP and Magnesium PDB-6hzm: Cryo-EM structure of the ABCG2 E211Q mutant bound to ATP and Magnesium (alternative placement of Magnesium into the cryo-EM density) Method: EM (single particle) / Resolution: 3.09 Å 0196 6hco EMDB-0196, PDB-6hco: Cryo-EM structure of the ABCG2 E211Q mutant bound to estrone 3-sulfate and 5D3-Fab Method: EM (single particle) / Resolution: 3.58 Å
Chemicals	ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying moleculeYM ChemComp-MG: Unknown entry ChemComp-FY5: estrone 3-sulfate / medication, hormoneYM ChemComp-HOH: WATER
Source	homo sapiens (human) mus musculus (house mouse)
Keywords	MEMBRANE PROTEIN / Multidrug transporter / cancer