PDBsum entry 3uf8

Isomerase, protein binding

PDB id: 3uf8

Contents

Protein chain

192 a.a.

Ligands

FK5

Waters ×265

PDB id:

3uf8

Name:

Isomerase, protein binding

Title:

Crystal structure of a smt fusion peptidyl-prolyl cis-trans isomerase with a g95a surface mutation from burkholderia pseudomallei complexed with fk506

Structure:

Ubiquitin-like protein smt3, peptidyl-prolyl cis-trans isomerase. Chain: a. Fragment: q12306 residues 13-98, q3jk38 residues 2-113. Engineered: yes. Mutation: yes. Other_details: fusion protein

Source:

Saccharomyces cerevisiae, burkholderia pseudomallei. Baker's yeast. Organism_taxid: 559292, 320372. Strain: 1710b, s288c. Gene: burps1710b_a0907, smt3, ydr510w, d9719.15. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.50Å R-factor: 0.158 R-free: 0.183

Authors:

Seattle Structural Genomics Center For Infectious Disease (Ssgcid)

Key ref:

D.W.Begley et al. (2014). A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins. Antimicrob Agents Chemother, 58, 1458-1467. PubMed id: 24366729 DOI: 10.1128/AAC.01875-13

Date:

31-Oct-11 Release date: 09-Nov-11

Protein chain

Q12306  (SMT3_YEAST) -  Ubiquitin-like protein SMT3 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 101 a.a.

Struc: 192 a.a.*

Protein chain

Q3JK38  (Q3JK38_BURP1) -  Peptidyl-prolyl cis-trans isomerase from Burkholderia pseudomallei (strain 1710b)

Seq: 113 a.a.

Struc: 192 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.5.2.1.8 - peptidylprolyl isomerase.
• Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1128/AAC.01875-13

Antimicrob Agents Chemother 58:1458-1467 (2014)

PubMed id: 24366729

A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins.

D.W.Begley, D.Fox, D.Jenner, C.Juli, P.G.Pierce, J.Abendroth, M.Muruthi, K.Safford, V.Anderson, K.Atkins, S.R.Barnes, S.O.Moen, A.C.Raymond, R.Stacy, P.J.Myler, B.L.Staker, N.J.Harmer, I.H.Norville, U.Holzgrabe, M.Sarkar-Tyson, T.E.Edwards, D.D.Lorimer.

ABSTRACT

Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery.