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- EMDB-41409: Cryo-EM structure of PCSK9 mimic HIT01-K21Q-R218E with AMG145 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-41409
TitleCryo-EM structure of PCSK9 mimic HIT01-K21Q-R218E with AMG145 Fab
Map data
Sample
  • Complex: HIT01-K21Q-R218E with AMG145 Fab
KeywordsPCSK9 mimic / vaccine / STRUCTURAL PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.48 Å
AuthorsCheng J / Kwong PD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Cell Rep / Year: 2024
Title: Cholesterol reduction by immunization with a PCSK9 mimic.
Authors: Baoshan Zhang / Gwo-Yu Chuang / Andrea Biju / Daniel Biner / Jiaxuan Cheng / Yiran Wang / Saran Bao / Cara W Chao / Haotian Lei / Tracy Liu / Alexandra F Nazzari / Yongping Yang / Tongqing ...Authors: Baoshan Zhang / Gwo-Yu Chuang / Andrea Biju / Daniel Biner / Jiaxuan Cheng / Yiran Wang / Saran Bao / Cara W Chao / Haotian Lei / Tracy Liu / Alexandra F Nazzari / Yongping Yang / Tongqing Zhou / Steven J Chen / Xuejun Chen / Wing-Pui Kong / Li Ou / Danealle K Parchment / Edward K Sarfo / HaoMin SiMa / John-Paul Todd / Shuishu Wang / Ruth A Woodward / Cheng Cheng / Reda Rawi / John R Mascola / Peter D Kwong /
Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue ...Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively. Immunization of cynomolgus macaques with HIT01-K21Q-R218E, a cleavage-resistant variant, elicits high-titer PCSK9-directed antibody responses and significantly reduces serum levels of cholesterol 2 weeks after each immunization. However, HIT01-K21Q-R218E immunizations also increase serum PCSK9 levels by up to 5-fold, likely due to PCSK9-binding antibodies altering the half-life of PCSK9. While vaccination with a PCSK9 mimic can induce antibodies that block interactions of PCSK9 with the LDL receptor, PCSK9-binding antibodies appear to alter homeostatic levels of PCSK9, thereby confounding its vaccine impact. Our results nevertheless suggest a mechanism for increasing the half-life of soluble regulatory factors by vaccination.
History
DepositionAug 1, 2023-
Header (metadata) releaseMay 22, 2024-
Map releaseMay 22, 2024-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41409.png

Downloads & links

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Map

FileDownload / File: emd_41409.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.92 Å
Density
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.06809025 - 0.28004268
Average (Standard dev.)0.0021140669 (±0.0131561775)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 235.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_41409_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_41409_half_map_2.map
Projections & Slices
AxesZYX

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Sample components

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Entire : HIT01-K21Q-R218E with AMG145 Fab

EntireName: HIT01-K21Q-R218E with AMG145 Fab
Components
  • Complex: HIT01-K21Q-R218E with AMG145 Fab

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Supramolecule #1: HIT01-K21Q-R218E with AMG145 Fab

SupramoleculeName: HIT01-K21Q-R218E with AMG145 Fab / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 66.47 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
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:

3h42

Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.48 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 328000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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