6hd1
human STEAP4 bound to NADPH, FAD and heme.
Structural highlights
Function[STEA4_HUMAN] Metalloreductase that has the ability to reduce both Fe(3+) to Fe(2+) and Cu(2+) to Cu(1+) (By similarity). Uses NADP(+) as acceptor (By similarity). Plays a role in systemic metabolic homeostasis, integrating inflammatory and metabolic responses (By similarity). Associated with obesity and insulin-resistance (PubMed:18430367, PubMed:18381574). Involved in inflammatory arthritis, through the regulation of inflammatory cytokines (PubMed:19660107). Inhibits anchorage-independent cell proliferation (PubMed:19787193).[1] [2] [3] [4] Publication Abstract from PubMedEnzymes of the six-transmembrane epithelial antigen of the prostate (STEAP) family reduce Fe(3+) and Cu(2+) 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(3+)-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. Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction.,Oosterheert W, van Bezouwen LS, Rodenburg RNP, Granneman J, Forster F, Mattevi A, Gros P Nat Commun. 2018 Oct 18;9(1):4337. doi: 10.1038/s41467-018-06817-7. PMID:30337524[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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