6Y9B

Cryo-EM structure of trimeric human STEAP1 bound to three Fab120.545 fragments

6Y9B の概要

• エントリーDOI: 10.2210/pdb6y9b/pdb
• EMDBエントリー: 10735
• 分子名称: Metalloreductase STEAP1, Fab120.545 light chain, Fab120.545 heavy chain, ... (5 entities in total)
• 機能のキーワード: integral membrane protein heme-binding protein oxidoreductase antibody-antigen complex, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 287657.92

構造登録者

Oosterheert, W.,Gros, P. (登録日: 2020-03-06, 公開日: 2020-05-20, 最終更新日: 2024-10-16)

主引用文献

Oosterheert, W.,Gros, P.
Cryo-electron microscopy structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1 (STEAP1).
J.Biol.Chem., 295:9502-9512, 2020

PubMed Abstract: Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly up-regulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases. It shares sequence homology with three enzymes (STEAP2-STEAP4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ∼3.0-Å cryo-EM structure of trimeric human STEAP1 bound to three antigen-binding fragments (Fabs) of the clinically used antibody mAb120.545. The structure revealed that STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells revealed that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, suggesting that STEAP1 functions as a ferric reductase in STEAP heterotrimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and may be useful in the design of new therapeutic strategies to target STEAP1 in cancer.

PubMed: 32409586
DOI: 10.1074/jbc.RA120.013690

実験手法

ELECTRON MICROSCOPY (2.97 Å)