- EMDB-16353: Structure of SLC40/ferroportin in complex with synthetic nanobody... -
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基本情報
登録情報
データベース: EMDB / ID: EMD-16353
タイトル
Structure of SLC40/ferroportin in complex with synthetic nanobody Sy3 in occluded conformation
マップデータ
試料
複合体: Complex of ferroportin with synthetic nanobody
タンパク質・ペプチド: Solute carrier family 40 member 1
タンパク質・ペプチド: Sybody3
機能・相同性
機能・相同性情報
spleen trabecula formation / iron ion export across plasma membrane / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages) / Defective CP causes aceruloplasminemia (ACERULOP) / Metal ion SLC transporters / lymphocyte homeostasis / iron ion transmembrane transporter activity / iron ion transmembrane transport / ferrous iron transmembrane transporter activity ...spleen trabecula formation / iron ion export across plasma membrane / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages) / Defective CP causes aceruloplasminemia (ACERULOP) / Metal ion SLC transporters / lymphocyte homeostasis / iron ion transmembrane transporter activity / iron ion transmembrane transport / ferrous iron transmembrane transporter activity / endothelium development / peptide hormone binding / establishment of localization in cell / Iron uptake and transport / multicellular organismal-level iron ion homeostasis / synaptic vesicle / basolateral plasma membrane / intracellular iron ion homeostasis / transcription by RNA polymerase II / apoptotic process / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol 類似検索 - 分子機能
ジャーナル: Elife / 年: 2023 タイトル: Structures of ferroportin in complex with its specific inhibitor vamifeport. 著者: Elena Farah Lehmann / Márton Liziczai / Katarzyna Drożdżyk / Patrick Altermatt / Cassiano Langini / Vania Manolova / Hanna Sundstrom / Franz Dürrenberger / Raimund Dutzler / Cristina Manatschal / 要旨: A central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular iron exporter, and the peptide hormone hepcidin, which inhibits Fe transport and induces ...A central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular iron exporter, and the peptide hormone hepcidin, which inhibits Fe transport and induces internalization and degradation of FPN. Dysregulation of the FPN/hepcidin axis leads to diverse pathological conditions, and consequently, pharmacological compounds that inhibit FPN-mediated iron transport are of high clinical interest. Here, we describe the cryo-electron microscopy structures of human FPN in complex with synthetic nanobodies and vamifeport (VIT-2763), the first clinical-stage oral FPN inhibitor. Vamifeport competes with hepcidin for FPN binding and is currently in clinical development for β-thalassemia and sickle cell disease. The structures display two distinct conformations of FPN, representing outward-facing and occluded states of the transporter. The vamifeport site is located in the center of the protein, where the overlap with hepcidin interactions underlies the competitive relationship between the two molecules. The introduction of point mutations in the binding pocket of vamifeport reduces its affinity to FPN, emphasizing the relevance of the structural data. Together, our study reveals conformational rearrangements of FPN that are of potential relevance for transport, and it provides initial insight into the pharmacological targeting of this unique iron efflux transporter.
全体 : Complex of ferroportin with synthetic nanobody
全体
名称: Complex of ferroportin with synthetic nanobody
要素
複合体: Complex of ferroportin with synthetic nanobody
タンパク質・ペプチド: Solute carrier family 40 member 1
タンパク質・ペプチド: Sybody3
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超分子 #1: Complex of ferroportin with synthetic nanobody
超分子
名称: Complex of ferroportin with synthetic nanobody / タイプ: complex / ID: 1 / キメラ: Yes / 親要素: 0 / 含まれる分子: all 詳細: Ferroportin was expressed in human derived HEK cells, whereas the synthetic nanobody was expressed in bacterial cell culture. The two were purified separately and mixed shortly before vitrification
由来(天然)
生物種: Homo sapiens (ヒト)
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分子 #1: Solute carrier family 40 member 1
分子
名称: Solute carrier family 40 member 1 / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO