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Title | Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction. |
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Journal, issue, pages | Nat Commun, Vol. 9, Issue 1, Page 4337, Year 2018 |
Publish date | Oct 18, 2018 |
![]() | Wout Oosterheert / Laura S van Bezouwen / Remco N P Rodenburg / Joke Granneman / Friedrich Förster / Andrea Mattevi / Piet Gros / ![]() ![]() |
PubMed Abstract | Enzymes of the six-transmembrane epithelial antigen of the prostate (STEAP) family reduce Fe and Cu ions to facilitate metal-ion uptake by mammalian cells. STEAPs are highly upregulated in several ...Enzymes of the six-transmembrane epithelial antigen of the prostate (STEAP) family reduce Fe and Cu ions to facilitate metal-ion uptake by mammalian cells. STEAPs are highly upregulated in several types of cancer, making them potential therapeutic targets. However, the structural basis for STEAP-catalyzed electron transfer through an array of cofactors to metals at the membrane luminal side remains elusive. Here, we report cryo-electron microscopy structures of human STEAP4 in absence and presence of Fe-NTA. Domain-swapped, trimeric STEAP4 orients NADPH bound to a cytosolic domain onto axially aligned flavin-adenine dinucleotide (FAD) and a single b-type heme that cross the transmembrane-domain to enable electron transfer. Substrate binding within a positively charged ring indicates that iron gets reduced while in complex with its chelator. These molecular principles of iron reduction provide a basis for exploring STEAPs as therapeutic targets. |
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Methods | EM (single particle) |
Resolution | 3.1 - 3.8 Å |
Structure data | |
Chemicals | ![]() ChemComp-NAP: ![]() ChemComp-HEM: ![]() ChemComp-FAD: ![]() ChemComp-NAG: ![]() ChemComp-44E: |
Source |
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![]() | MEMBRANE PROTEIN / Enzyme / Metalloreductase / Electron Transfer / Cofactor-binding |