PDBsum entry 5eud

Lyase

PDB id: 5eud

Contents

Protein chains

454 a.a.

Ligands

PO4 ×2

5S6 ×2

Waters ×423

PDB id:

5eud

Name:

Lyase

Title:

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

Structure:

Putative sphingosine-1-phosphate lyase. Chain: a, b. Engineered: yes. Mutation: yes

Source:

Symbiobacterium thermophilum (strain t / iam 14863). Organism_taxid: 292459. Strain: t / iam 14863. Gene: sth1274. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.24Å R-factor: 0.164 R-free: 0.206

Authors:

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

Key ref:

M.A.Argiriadi et al. (2016). Creation of a S1P Lyase bacterial surrogate for structure-based drug design. Bioorg Med Chem Lett, 26, 2293-2296. PubMed id: 27013389 DOI: 10.1016/j.bmcl.2016.02.084

Date:

18-Nov-15 Release date: 16-Mar-16

Protein chains

Q67PY4  (Q67PY4_SYMTH) -  Putative sphingosine-1-phosphate lyase from Symbiobacterium thermophilum (strain T / IAM 14863)

Seq: 507 a.a.

Struc: 454 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

DOI no: 10.1016/j.bmcl.2016.02.084

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

PubMed id: 27013389

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

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

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.