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- EMDB-42124: Cryo-EM structure of human STEAP1 in complex with AMG 509 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-42124
TitleCryo-EM structure of human STEAP1 in complex with AMG 509 Fab
Map datasharpened map
Sample
  • Complex: complex of human STEAP1 with AMG 509 Fab
    • Protein or peptide: Metalloreductase STEAP1
    • Protein or peptide: AMG 509 anti-STEAP1 Fab, heavy chain
    • Protein or peptide: AMG 509 anti-STEAP1 Fab, light chain
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDEFlavin adenine dinucleotide
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: water
Keywordsmembrane protein / antibody / cancer / membrane protein-immune system complex
Function / homology
Function and homology information


cell-cell junction / endosome membrane / endosome / heme binding / membrane / metal ion binding / plasma membrane
Similarity search - Function
Ferric reductase transmembrane component-like domain / Ferric reductase like transmembrane component
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsLi F / Bailis JM
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Cancer Discov / Year: 2024
Title: AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer.
Authors: Olivier Nolan-Stevaux / Cong Li / Lingming Liang / Jinghui Zhan / Juan Estrada / Tao Osgood / Fei Li / Hanzhi Zhang / Ryan Case / Christopher M Murawsky / Bram Estes / Gregory L Moore / ...Authors: Olivier Nolan-Stevaux / Cong Li / Lingming Liang / Jinghui Zhan / Juan Estrada / Tao Osgood / Fei Li / Hanzhi Zhang / Ryan Case / Christopher M Murawsky / Bram Estes / Gregory L Moore / Matthew J Bernett / Umesh Muchhal / John R Desjarlais / Binnaz K Staley / Jennitte Stevens / Keegan S Cooke / Famke Aeffner / Oliver Thomas / Julia Stieglmaier / Jae-Lyun Lee / Angela Coxon / Julie M Bailis /
Abstract: The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We ...The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment.
SIGNIFICANCE: Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy ...SIGNIFICANCE: Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5.
History
DepositionSep 26, 2023-
Header (metadata) releaseNov 22, 2023-
Map releaseNov 22, 2023-
UpdateJan 24, 2024-
Current statusJan 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42124.png

Downloads & links

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Map

FileDownload / File: emd_42124.map.gz / Format: CCP4 / Size: 361.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.1436234 - 2.179612
Average (Standard dev.)-0.0003019661 (±0.025092438)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions456456456
Spacing456456456
CellA=B=C: 392.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map B

Fileemd_42124_half_map_1.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_42124_half_map_2.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : complex of human STEAP1 with AMG 509 Fab

EntireName: complex of human STEAP1 with AMG 509 Fab
Components
  • Complex: complex of human STEAP1 with AMG 509 Fab
    • Protein or peptide: Metalloreductase STEAP1
    • Protein or peptide: AMG 509 anti-STEAP1 Fab, heavy chain
    • Protein or peptide: AMG 509 anti-STEAP1 Fab, light chain
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDEFlavin adenine dinucleotide
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: water

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Supramolecule #1: complex of human STEAP1 with AMG 509 Fab

SupramoleculeName: complex of human STEAP1 with AMG 509 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168 KDa

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Macromolecule #1: Metalloreductase STEAP1

MacromoleculeName: Metalloreductase STEAP1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.21527 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MESRKDITNQ EELWKMKPRR NLEEDDYLHK DTGETSMLKR PVLLHLHQTA HADEFDCPSE LQHTQELFPQ WHLPIKIAAI IASLTFLYT LLREVIHPLA TSHQQYFYKI PILVINKVLP MVSITLLALV YLPGVIAAIV QLHNGTKYKK FPHWLDKWML T RKQFGLLS ...String:
MESRKDITNQ EELWKMKPRR NLEEDDYLHK DTGETSMLKR PVLLHLHQTA HADEFDCPSE LQHTQELFPQ WHLPIKIAAI IASLTFLYT LLREVIHPLA TSHQQYFYKI PILVINKVLP MVSITLLALV YLPGVIAAIV QLHNGTKYKK FPHWLDKWML T RKQFGLLS FFFAVLHAIY SLSYPMRRSY RYKLLNWAYQ QVQQNKEDAW IEHDVWRMEI YVSLGIVGLA ILALLAVTSI PS VSDSLTW REFHYIQSKL GIVSLLLGTI HALIFAWNKW IDIKQFVWYT PPTFMIAVFL PIVVLIFKSI LFLPCLRKKI LKI RHGWED VTKINKTEIC SQLGGGGSDY KDDDDK

UniProtKB: STEAP1 protein

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Macromolecule #2: AMG 509 anti-STEAP1 Fab, heavy chain

MacromoleculeName: AMG 509 anti-STEAP1 Fab, heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.227457 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLVQSGAE VKKPGASVKV SCKASGYTFS TYWIEWVRQA PGQRLEWMGE ILPGSGQTDF NEKFQGRVTF TADTSSDTAY MELSSLRSE DTAVYYCTRW GYYGTRGYFN VWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS

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Macromolecule #3: AMG 509 anti-STEAP1 Fab, light chain

MacromoleculeName: AMG 509 anti-STEAP1 Fab, light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.391014 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVLTQSPAT LSLSPGERAT LSCRASSSVS YMHWFQQKPG QAPRLLIYST SNLASGIPAR FSGSGSGTDY TLTISSLEPE DFAVYYCQQ RRSFPYTFGQ GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
EIVLTQSPAT LSLSPGERAT LSCRASSSVS YMHWFQQKPG QAPRLLIYST SNLASGIPAR FSGSGSGTDY TLTISSLEPE DFAVYYCQQ RRSFPYTFGQ GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC

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Macromolecule #4: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

MacromoleculeName: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 4 / Number of copies: 3 / Formula: LBN
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM / POPC

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Macromolecule #5: FLAVIN-ADENINE DINUCLEOTIDE

MacromoleculeName: FLAVIN-ADENINE DINUCLEOTIDE / type: ligand / ID: 5 / Number of copies: 3 / Formula: FAD
Molecular weightTheoretical: 785.55 Da
Chemical component information

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM / Flavin adenine dinucleotide

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Macromolecule #6: PROTOPORPHYRIN IX CONTAINING FE

MacromoleculeName: PROTOPORPHYRIN IX CONTAINING FE / type: ligand / ID: 6 / Number of copies: 3 / Formula: HEM
Molecular weightTheoretical: 616.487 Da
Chemical component information

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE / Heme B

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2.3 mg/mL
BufferpH: 7.5
GridMaterial: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 47.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6y9b

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 203530
FSC plot (resolution estimation)

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