6Y9B
Cryo-EM structure of trimeric human STEAP1 bound to three Fab120.545 fragments
Summary for 6Y9B
| Entry DOI | 10.2210/pdb6y9b/pdb |
| EMDB information | 10735 |
| Descriptor | Metalloreductase STEAP1, Fab120.545 light chain, Fab120.545 heavy chain, ... (5 entities in total) |
| Functional Keywords | integral membrane protein heme-binding protein oxidoreductase antibody-antigen complex, membrane protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 9 |
| Total formula weight | 287657.92 |
| Authors | Oosterheert, W.,Gros, P. (deposition date: 2020-03-06, release date: 2020-05-20, Last modification date: 2024-10-16) |
| Primary citation | 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 Cited by 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: 32409586DOI: 10.1074/jbc.RA120.013690 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.97 Å) |
Structure validation
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