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- EMDB-42601: CryoEM structure of Kappa Opioid Receptor bound to a semi-peptide... -

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Basic information

Entry
Database: EMDB / ID: EMD-42601
TitleCryoEM structure of Kappa Opioid Receptor bound to a semi-peptide and Gi1
Map data
Sample
  • Complex: Kappa Opioid Receptor in complex with Gi1 heterotrimer and a peptide ligand
KeywordsGPCR / KAPPA OPIOID Receptor / ROSETTA / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.54 Å
AuthorsFay JF / Che T
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143061 United States
CitationJournal: Nat Commun / Year: 2023
Title: Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.
Authors: Edin Muratspahić / Kristine Deibler / Jianming Han / Nataša Tomašević / Kirtikumar B Jadhav / Aina-Leonor Olivé-Marti / Nadine Hochrainer / Roland Hellinger / Johannes Koehbach / ...Authors: Edin Muratspahić / Kristine Deibler / Jianming Han / Nataša Tomašević / Kirtikumar B Jadhav / Aina-Leonor Olivé-Marti / Nadine Hochrainer / Roland Hellinger / Johannes Koehbach / Jonathan F Fay / Mohammad Homaidur Rahman / Lamees Hegazy / Timothy W Craven / Balazs R Varga / Gaurav Bhardwaj / Kevin Appourchaux / Susruta Majumdar / Markus Muttenthaler / Parisa Hosseinzadeh / David J Craik / Mariana Spetea / Tao Che / David Baker / Christian W Gruber /
Abstract: Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single ...Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA-KOR-Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.
History
DepositionNov 2, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42601.png

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Map

FileDownload / File: emd_42601.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.88 Å
Density
Contour LevelBy AUTHOR: 0.09
Minimum - Maximum-0.06527514 - 2.3898869
Average (Standard dev.)0.0005063024 (±0.013153957)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 253.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_42601_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram (log scale)

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Half map: #2

Fileemd_42601_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Kappa Opioid Receptor in complex with Gi1 heterotrimer and a pept...

EntireName: Kappa Opioid Receptor in complex with Gi1 heterotrimer and a peptide ligand
Components
  • Complex: Kappa Opioid Receptor in complex with Gi1 heterotrimer and a peptide ligand

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Supramolecule #1: Kappa Opioid Receptor in complex with Gi1 heterotrimer and a pept...

SupramoleculeName: Kappa Opioid Receptor in complex with Gi1 heterotrimer and a peptide ligand
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: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 4027 / Average electron dose: 49.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.9 µm / Nominal defocus min: 0.2 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.54 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 491092
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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