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- PDB-7tai: Structure of STEAP2 in complex with ligands -

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Basic information

Entry
Database: PDB / ID: 7tai
TitleStructure of STEAP2 in complex with ligands
ComponentsMetalloreductase STEAP2
KeywordsOXIDOREDUCTASE / membrane-embedded oxidoreductase / membrane protein
Function / homology
Function and homology information


copper ion import across plasma membrane / Oxidoreductases; Oxidizing metal ions; With NAD+ or NADP+ as acceptor / ferric-chelate reductase (NADPH) activity / cupric reductase activity / iron ion import across plasma membrane / regulated exocytosis / copper ion import / Transferrin endocytosis and recycling / Golgi to plasma membrane transport / trans-Golgi network transport vesicle ...copper ion import across plasma membrane / Oxidoreductases; Oxidizing metal ions; With NAD+ or NADP+ as acceptor / ferric-chelate reductase (NADPH) activity / cupric reductase activity / iron ion import across plasma membrane / regulated exocytosis / copper ion import / Transferrin endocytosis and recycling / Golgi to plasma membrane transport / trans-Golgi network transport vesicle / response to hormone / endocytosis / early endosome / endosome membrane / endosome / Golgi membrane / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Ferric reductase transmembrane component-like domain / Ferric reductase like transmembrane component / Pyrroline-5-carboxylate reductase, catalytic, N-terminal / NADP oxidoreductase coenzyme F420-dependent / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
CHOLESTEROL / FLAVIN-ADENINE DINUCLEOTIDE / PROTOPORPHYRIN IX CONTAINING FE / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Metalloreductase STEAP2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWang, L. / Chen, K.H. / Zhou, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD) United States
CitationJournal: Elife / Year: 2023
Title: Mechanism of stepwise electron transfer in six-transmembrane epithelial antigen of the prostate (STEAP) 1 and 2.
Authors: Kehan Chen / Lie Wang / Jiemin Shen / Ah-Lim Tsai / Ming Zhou / Gang Wu /
Abstract: Six transmembrane epithelial antigen of the prostate (STEAP) 1-4 are membrane-embedded hemoproteins that chelate a heme prosthetic group in a transmembrane domain (TMD). STEAP2-4, but not STEAP1, ...Six transmembrane epithelial antigen of the prostate (STEAP) 1-4 are membrane-embedded hemoproteins that chelate a heme prosthetic group in a transmembrane domain (TMD). STEAP2-4, but not STEAP1, have an intracellular oxidoreductase domain (OxRD) and can mediate cross-membrane electron transfer from NADPH via FAD and heme. However, it is unknown whether STEAP1 can establish a physiologically relevant electron transfer chain. Here, we show that STEAP1 can be reduced by reduced FAD or soluble cytochrome reductase that serves as a surrogate OxRD, providing the first evidence that STEAP1 can support a cross-membrane electron transfer chain. It is not clear whether FAD, which relays electrons from NADPH in OxRD to heme in TMD, remains constantly bound to the STEAPs. We found that FAD reduced by STEAP2 can be utilized by STEAP1, suggesting that FAD is diffusible rather than staying bound to STEAP2. We determined the structure of human STEAP2 in complex with NADP and FAD to an overall resolution of 3.2 Å by cryo-electron microscopy and found that the two cofactors bind STEAP2 similarly as in STEAP4, suggesting that a diffusible FAD is a general feature of the electron transfer mechanism in the STEAPs. We also demonstrated that STEAP2 reduces ferric nitrilotriacetic acid (Fe-NTA) significantly slower than STEAP1 and proposed that the slower reduction is due to the poor Fe-NTA binding to the highly flexible extracellular region in STEAP2. These results establish a solid foundation for understanding the function and mechanisms of the STEAPs.
History
DepositionDec 20, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Metalloreductase STEAP2
A: Metalloreductase STEAP2
C: Metalloreductase STEAP2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)179,38221
Polymers168,3463
Non-polymers11,03618
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 3 molecules BAC

#1: Protein Metalloreductase STEAP2 / Prostate cancer-associated protein 1 / Protein up-regulated in metastatic prostate cancer / PUMPCn ...Prostate cancer-associated protein 1 / Protein up-regulated in metastatic prostate cancer / PUMPCn / Six-transmembrane epithelial antigen of prostate 2 / SixTransMembrane protein of prostate 1


Mass: 56115.305 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STEAP2, PCANAP1, STAMP1, UNQ6507/PRO23203 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q8NFT2, Oxidoreductases; Oxidizing metal ions; With NAD+ or NADP+ as acceptor

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Non-polymers , 5 types, 18 molecules

#2: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE / Flavin adenine dinucleotide


Mass: 785.550 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H28N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-LBN / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / (2R)-2-[(9Z)-9-Octadecenoyloxy]-3-(palmitoyloxy)propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#6: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Homo-trimeric complex of STEAP2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.056 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: OTHER

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: TUNGSTEN HAIRPIN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 305849 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411448
ELECTRON MICROSCOPYf_angle_d0.66815666
ELECTRON MICROSCOPYf_dihedral_angle_d11.9121950
ELECTRON MICROSCOPYf_chiral_restr0.0461752
ELECTRON MICROSCOPYf_plane_restr0.0052025

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