5EUD

S1P Lyase Bacterial Surrogate bound to N-(1-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)-2-((4-methoxy-2,5-dimethylbenzyl)amino)ethyl)-5-methylisoxazole-3-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Creation of a S1P Lyase bacterial surrogate for structure-based drug design.

Argiriadi, M.A.Banach, D.Radziejewska, E.Marchie, S.DiMauro, J.Dinges, J.Dominguez, E.Hutchins, C.Judge, R.A.Queeney, K.Wallace, G.Harris, C.M.

(2016) Bioorg Med Chem Lett 26: 2293-2296

  • DOI: https://doi.org/10.1016/j.bmcl.2016.02.084
  • Primary Citation of Related Structures:  
    5EUD, 5EUE

  • PubMed Abstract: 

    S1P Lyase (SPL) has been described as a drug target in the treatment of autoimmune diseases. It plays an important role in maintaining intracellular levels of S1P thereby affecting T cell egress from lymphoid tissues. Several groups have already published approaches to inhibit S1P Lyase with small molecules, which in turn increase endogenous S1P concentrations resulting in immunosuppression. The use of structural biology has previously aided SPL inhibitor design. Novel construct design is at times necessary to provide a reagent for protein crystallography. Here we present a chimeric bacterial protein scaffold used for protein X-ray structures in the presence of early small molecule inhibitors. Mutations were introduced to the bacterial SPL from Symbiobacterium thermophilum which mimic the human enzyme. As a result, two mutant StSPL crystal structures resolved to 2.8Å and 2.2Å resolutions were solved and provide initial structural hypotheses for an isoxazole chemical series, whose optimization is discussed in the accompanying paper.


  • Organizational Affiliation

    AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA 01605, USA. Electronic address: maria.argiriadi@abbvie.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Putative sphingosine-1-phosphate lyase
A, B
514Symbiobacterium thermophilum IAM 14863Mutation(s): 4 
Gene Names: STH1274
UniProt
Find proteins for Q67PY4 (Symbiobacterium thermophilum (strain T / IAM 14863))
Explore Q67PY4 
Go to UniProtKB:  Q67PY4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ67PY4
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5S6
Query on 5S6

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A]
~{N}-[(1~{S})-2-[(4-methoxy-2,5-dimethyl-phenyl)methylamino]-1-[4-(3-oxidanylprop-1-ynyl)phenyl]ethyl]-5-methyl-1,2-oxazole-3-carboxamide
C26 H29 N3 O4
DNHSLHQHJBUNLI-XMMPIXPASA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A],
F [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
LLP
Query on LLP
A, B
L-PEPTIDE LINKINGC14 H22 N3 O7 PLYS
Binding Affinity Annotations 
IDSourceBinding Affinity
5S6 Binding MOAD:  5EUD IC50: 150 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.94α = 90
b = 85.126β = 90
c = 129.507γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
autoPROCdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-16
    Type: Initial release
  • Version 1.1: 2016-04-06
    Changes: Database references
  • Version 1.2: 2016-04-27
    Changes: Database references
  • Version 1.3: 2016-07-20
    Changes: Data collection
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.5: 2023-11-15
    Changes: Data collection