7AUZ

LTA4 hydrolase in complex with compound LYS006


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.4 of the entry. See complete history


Literature

Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A 4 Hydrolase.

Markert, C.Thoma, G.Srinivas, H.Bollbuck, B.Luond, R.M.Miltz, W.Walchli, R.Wolf, R.Hinrichs, J.Bergsdorf, C.Azzaoui, K.Penno, C.A.Klein, K.Wack, N.Jager, P.Hasler, F.Beerli, C.Loetscher, P.Dawson, J.Wieczorek, G.Numao, S.Littlewood-Evans, A.Rohn, T.A.

(2021) J Med Chem 64: 1889-1903

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c01955
  • Primary Citation of Related Structures:  
    7AUZ, 7AV0, 7AV1, 7AV2

  • PubMed Abstract: 

    The cytosolic metalloenzyme leukotriene A 4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B 4 (LTB 4 ). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB 4 generation at low exposures in vivo , LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Leukotriene A-4 hydrolase613Homo sapiensMutation(s): 0 
EC: 3.3.2.6 (PDB Primary Data), 3.4.11.4 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P09960 (Homo sapiens)
Explore P09960 
Go to UniProtKB:  P09960
PHAROS:  P09960
GTEx:  ENSG00000111144 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09960
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RZE (Subject of Investigation/LOI)
Query on RZE

Download Ideal Coordinates CCD File 
I [auth A](3~{S})-3-azanyl-4-[5-[4-(5-chloranyl-3-fluoranyl-pyridin-2-yl)oxyphenyl]-1,2,3,4-tetrazol-2-yl]butanoic acid
C16 H14 Cl F N6 O3
ZEGMEJVULDALSH-NSHDSACASA-N
YB
Query on YB

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
YTTERBIUM (III) ION
Yb
AWSFICBXMUKWSK-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
C [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
RZE BindingDB:  7AUZ IC50: min: 0.12, max: 167 (nM) from 5 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.189α = 90
b = 86.7β = 90
c = 98.962γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted RZEClick on this verticalbar to view details

Entry History 

Deposition Data

  • Released Date: 2021-02-17 
  • Deposition Author(s): Srinivas, H.

Revision History  (Full details and data files)

  • Version 1.0: 2021-02-17
    Type: Initial release
  • Version 1.1: 2021-02-24
    Changes: Database references
  • Version 1.2: 2021-03-03
    Changes: Database references
  • Version 1.3: 2021-03-10
    Changes: Database references
  • Version 1.4: 2024-01-31
    Changes: Data collection, Database references, Refinement description