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- PDB-8ucd: Cryo-EM structure of human STEAP1 in complex with AMG 509 Fab -

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Basic information

Entry
Database: PDB / ID: 8ucd
TitleCryo-EM structure of human STEAP1 in complex with AMG 509 Fab
Components
  • (AMG 509 anti-STEAP1 Fab, ...) x 2
  • Metalloreductase STEAP1
Keywordsmembrane protein/immune system / membrane 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
FLAVIN-ADENINE DINUCLEOTIDE / PROTOPORPHYRIN IX CONTAINING FE / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / STEAP1 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsLi, F. / Bailis, J.M. / Zhang, H.
Funding support United States, 1items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Metalloreductase STEAP1
B: Metalloreductase STEAP1
C: Metalloreductase STEAP1
H: AMG 509 anti-STEAP1 Fab, heavy chain
L: AMG 509 anti-STEAP1 Fab, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,75114
Polymers167,2645
Non-polymers6,4869
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 3 molecules ABC

#1: Protein Metalloreductase STEAP1


Mass: 41215.270 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STEAP1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9UHE8

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Antibody , 2 types, 2 molecules HL

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


Mass: 20227.457 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody AMG 509 anti-STEAP1 Fab, light chain


Mass: 23391.014 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Non-polymers , 4 types, 10 molecules

#4: 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
#5: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE / Flavin adenine dinucleotide


Mass: 785.550 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C27H33N9O15P2 / Comment: FAD*YM
#6: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: complex of human STEAP1 with AMG 509 Fab / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.168 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 2.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in.
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingElectron dose: 47 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 203530 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028324
ELECTRON MICROSCOPYf_angle_d0.57711395
ELECTRON MICROSCOPYf_dihedral_angle_d11.8171191
ELECTRON MICROSCOPYf_chiral_restr0.0391251
ELECTRON MICROSCOPYf_plane_restr0.0041317

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