6HCY

human STEAP4 bound to NADP, FAD, heme and Fe(III)-NTA.

Summary for 6HCY

• Entry DOI: 10.2210/pdb6hcy/pdb
• EMDB information: 0199
• Descriptor: Metalloreductase STEAP4, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: enzyme, metalloreductase, electron transfer, cofactor-binding, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 164313.03

Authors

Oosterheert, W.,van Bezouwen, L.S.,Rodenburg, R.N.P.,Forster, F.,Mattevi, A.,Gros, P. (deposition date: 2018-08-17, release date: 2018-10-24, Last modification date: 2024-10-23)

Primary citation

Oosterheert, W.,van Bezouwen, L.S.,Rodenburg, R.N.P.,Granneman, J.,Forster, F.,Mattevi, A.,Gros, P.
Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction.
Nat Commun, 9:4337-4337, 2018

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 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.

PubMed: 30337524
DOI: 10.1038/s41467-018-06817-7

Experimental method

ELECTRON MICROSCOPY (3.1 Å)