6UF0

Crystal structure of N-(4-((4-methoxy-N-(2,2,2-trifluoroethyl)phenyl)sulfonamido)isoquinolin-1-yl)-N-((4-methoxyphenyl)sulfonyl)glycine bound to human Keap1 Kelch domain

PDB DOI: https://doi.org/10.2210/pdb6UF0/pdb

Classification: PROTEIN BINDING
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2019-09-23 Released: 2019-12-18
Deposition Author(s): Lazzara, P.R., David, B.P., Ankireddy, A., Richardson, B.G., Dye, K., Ratia, K.M., Reddy, S.P., Moore, T.W.
Funding Organization(s): National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS), National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.96 Å
R-Value Free: 0.222
R-Value Work: 0.179
R-Value Observed: 0.181

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability.

Lazzara, P.R., David, B.P., Ankireddy, A., Richardson, B.G., Dye, K., Ratia, K.M., Reddy, S.P., Moore, T.W.

(2020) J Med Chem 63: 6547-6560

PubMed: 31682434 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.9b01074
Primary Citation of Related Structures:
6UF0

PubMed Abstract:
Pharmacological activation of NRF2 (nuclear factor erythroid 2-related factor 2) arises from blocking the interaction of NRF2 with its negative regulator, KEAP1 (Kelch-like ECH-associated protein 1). We previously reported an isoquinoline-based NRF2 activator, but this compound showed negative logD _7.4 and a -2 charge at physiological pH, which may have limited its membrane permeability. In this work, we report potent, metabolically stable analogs that result from replacing a carboxymethyl group at the 4-position with a fluoroalkyl group.

Macromolecule Content

Total Structure Weight: 64.94 kDa
Atom Count: 4,788
Modelled Residue Count: 570
Deposited Residue Count: 580
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Kelch-like ECH-associated protein 1	A, B	290	Homo sapiens	Mutation(s): 2 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

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
Q5V (Subject of Investigation/LOI) Query on Q5V Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	N-[(4-methoxyphenyl)sulfonyl]-N-(4-{[(4-methoxyphenyl)sulfonyl](2,2,2-trifluoroethyl)amino}isoquinolin-1-yl)glycine C₂₇ H₂₄ F₃ N₃ O₈ S₂ UVJKKKIWFDQRIO-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
Q5Y (Subject of Investigation/LOI) Query on Q5Y Download Ideal Coordinates CCD File SDF format, chain L [auth B] MOL2 format, chain L [auth B] mmCIF format, chain L [auth B]	L [auth B]	N-[(4-methoxyphenyl)sulfonyl]-N-(4-{[(4-methoxyphenyl)sulfonyl]amino}naphthalen-1-yl)glycine C₂₆ H₂₄ N₂ O₈ S₂ NVQFDGYHTTZFJR-UHFFFAOYSA-N		Interactions Focus chain L [auth B] Interactions & Density Focus chain L [auth B]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
FMT Query on FMT 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 J [auth A] SDF format, chain M [auth B] SDF format, chain N [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 J [auth A] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B]	D [auth A] E [auth A] G [auth A] H [auth A] I [auth A] D [auth A], E [auth A], G [auth A], H [auth A], I [auth A], J [auth A], M [auth B], N [auth B]	FORMIC ACID C H₂ O₂ BDAGIHXWWSANSR-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain N [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain M [auth B] Focus chain N [auth B]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain O [auth B] MOL2 format, chain K [auth A] MOL2 format, chain O [auth B] mmCIF format, chain K [auth A] mmCIF format, chain O [auth B]	K [auth A], O [auth B]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Focus chain O [auth B] Interactions & Density Focus chain K [auth A] Focus chain O [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
Q5Y	BindingDB: 6UF0	Kd: 110 (nM) from 1 assay(s)
Q5Y	BindingDB: 6UF0	IC50: min: 61, max: 110 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.96 Å
R-Value Free: 0.222
R-Value Work: 0.179
R-Value Observed: 0.181
Space Group: I 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 105.712	α = 90
b = 57.35	β = 107.53
c = 130.425	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
Aimless	data scaling
MOLREP	phasing
PDB_EXTRACT	data extraction

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2019-12-18

Deposition Author(s):

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)	United States	1R01 AR069541-01A1
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)	United States	1R01 HL136946-01

Revision History (Full details and data files)

Version 1.0: 2019-12-18
Type: Initial release
Version 1.1: 2020-07-08
Changes: Database references
Version 1.2: 2023-10-11
Changes: Data collection, Database references, Derived calculations, Refinement description