6FMP

Keap1 - peptide complex

PDB DOI: https://doi.org/10.2210/pdb6FMP/pdb

Classification: PEPTIDE BINDING PROTEIN
Organism(s): Homo sapiens, synthetic construct
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2018-02-01 Released: 2018-08-08
Deposition Author(s): Talapatra, S.K., Kozielski, F., Wells, G., Georgakopoulos, N.D.
Funding Organization(s): UCL Secondment MRC PtD

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.92 Å
R-Value Free: 0.235
R-Value Work: 0.181
R-Value Observed: 0.183

wwPDB Validation 3D Report Full Report

This is version 2.1 of the entry. See complete history.

Literature

Modified Peptide Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction Incorporating Unnatural Amino Acids.

Georgakopoulos, N.D., Talapatra, S.K., Gatliff, J., Kozielski, F., Wells, G.

(2018) Chembiochem 19: 1810-1816

PubMed: 29927029 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/cbic.201800170
Primary Citation of Related Structures:
6FMP, 6FMQ

PubMed Abstract:
Noncovalent inhibitors of the Keap1-Nrf2 protein-protein interaction (PPI) have therapeutic potential in a range of disease states including neurodegenerative diseases (Parkinson's and Alzheimer's diseases), chronic obstructive pulmonary disease and various inflammatory conditions. By stalling Keap1-mediated ubiquitination of Nrf2, such compounds can enhance Nrf2 transcriptional activity and activate the expression of a range of genes with antioxidant response elements in their promoter regions. Keap1 inhibitors based on peptide and small-molecule templates have been identified. In this paper we develop the structure-activity relationships of the peptide series and identify a group of ligands incorporating unnatural amino acids that demonstrate improved binding affinity in fluorescence polarisation, differential scanning fluorimetry and isothermal titration calorimetry assays. These modified peptides have the potential for further development into peptidomimetic chemical probes to explore the role of Nrf2 in disease and as potential lead structures for drug development.

Organizational Affiliation

UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London, WC1N 1AX, UK.

Macromolecule Content

Total Structure Weight: 93.64 kDa
Atom Count: 4,610
Modelled Residue Count: 578
Deposited Residue Count: 836
Unique protein chains: 2

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Kelch-like ECH-associated protein 1	A, B	414	Homo sapiens	Mutation(s): 0 Gene Names: KEAP1, INRF2, KIAA0132, KLHL19
UniProt & NIH Common Fund Data Resources
Find proteins for Q14145 (Homo sapiens) Explore Q14145 Go to UniProtKB: Q14145
PHAROS: Q14145 GTEx: ENSG00000079999
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q14145
Sequence Annotations Expand
Reference Sequence

Find similar proteins by: Sequence | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
ACY-ASP-GLU-GLU-THR-GLY-GLU-PHE	C	8	synthetic construct	Mutation(s): 0
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain U [auth B] SDF format, chain L [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain U [auth B] MOL2 format, chain L [auth A]	J [auth A] K [auth A] L [auth A] S [auth B] T [auth B] J [auth A], K [auth A], L [auth A], S [auth B], T [auth B], U [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B] Interactions & Density Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain S [auth B] Focus chain T [auth B] Focus chain U [auth B]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain F [auth A] SDF format, chain O [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain F [auth A] MOL2 format, chain O [auth B]	D [auth A] E [auth A] F [auth A] G [auth A] H [auth A] D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], O [auth B], P [auth B], Q [auth B], R [auth B]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain M [auth B] SDF format, chain N [auth B] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B]	M [auth B], N [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain M [auth B] Focus chain N [auth B] Interactions & Density Focus chain M [auth B] Focus chain N [auth B]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain V [auth B] SDF format, chain W [auth C] MOL2 format, chain V [auth B] MOL2 format, chain W [auth C]	V [auth B], W [auth C]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain V [auth B] Focus chain W [auth C] Interactions & Density Focus chain V [auth B] Focus chain W [auth C]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.92 Å
R-Value Free: 0.235
R-Value Work: 0.181
R-Value Observed: 0.183
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 76.409	α = 90
b = 76.259	β = 90
c = 208.284	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
iMOSFLM	data reduction
SCALA	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Entry History & Funding Information

Deposition Data

Released Date: 2018-08-08

Deposition Author(s):

Funding Organization	Location	Grant Number
UCL Secondment MRC PtD	United Kingdom	530912

Revision History (Full details and data files)

Version 1.0: 2018-08-08
Type: Initial release
Version 1.1: 2018-09-12
Changes: Data collection, Database references
Version 2.0: 2023-03-15
Changes: Advisory, Atomic model, Database references, Derived calculations, Non-polymer description, Polymer sequence, Source and taxonomy, Structure summary
Version 2.1: 2024-02-07
Changes: Data collection, Refinement description

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Help and Resources

6FMP

Keap1 - peptide complex

Modified Peptide Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction Incorporating Unnatural Amino Acids.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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