6Y9B

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


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.97 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Cryo-electron microscopy structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1 (STEAP1).

Oosterheert, W.Gros, P.

(2020) J Biol Chem 295: 9502-9512

  • DOI: https://doi.org/10.1074/jbc.RA120.013690
  • Primary Citation of Related Structures:  
    6Y9B

  • 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.


  • Organizational Affiliation

    Crystal and Structural Chemistry, Bijvoet Centre for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands w.oosterheert@uu.nl p.gros@uu.nl.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Metalloreductase STEAP1A [auth C],
H [auth A],
I [auth B]
380Homo sapiensMutation(s): 0 
Gene Names: STEAP1PRSS24STEAP
EC: 1.16.1
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UHE8 (Homo sapiens)
Explore Q9UHE8 
Go to UniProtKB:  Q9UHE8
PHAROS:  Q9UHE8
GTEx:  ENSG00000164647 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UHE8
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fab120.545 light chainB [auth L],
F [auth M],
G [auth N]
220Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Fab120.545 heavy chainC [auth H],
D [auth I],
E [auth J]
238Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.97 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
RECONSTRUCTIONRELION3.1beta
MODEL REFINEMENTPHENIX1.17.1-3660

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Netherlands Organisation for Scientific Research (NWO)Netherlands731.015.201

Revision History  (Full details and data files)

  • Version 1.0: 2020-05-20
    Type: Initial release
  • Version 1.1: 2020-05-27
    Changes: Database references
  • Version 1.2: 2020-07-22
    Changes: Database references