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PDBsum entry 3s04

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protein ligands Protein-protein interface(s) links
Hydrolase/antibiotic PDB id
3s04
Jmol
Contents
Protein chains
209 a.a.
223 a.a.
Ligands
DSE-DAL-GLY-02V-
ALA-TYR
×2
02U ×2
RAM ×2
Waters ×57
PDB id:
3s04
Name: Hydrolase/antibiotic
Title: Crystal structure of escherichia coli type i signal peptidas complex with an arylomycin lipoglycopeptide antibiotic
Structure: Signal peptidase i. Chain: a, b. Fragment: periplasmic domain, unp residues 76-323. Synonym: spase i, leader peptidase i. Engineered: yes. Glyco-arylomycin. Chain: i, j
Source: Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: b2568, jw2552, lepb. Expressed in: escherichia coli. Expression_system_taxid: 469008. Streptomyces sp.. Organism_taxid: 1931
Resolution:
2.44Å     R-factor:   0.246     R-free:   0.265
Authors: M.Paetzel,C.Luo
Key ref: J.Liu et al. (2011). Synthesis and characterization of the arylomycin lipoglycopeptide antibiotics and the crystallographic analysis of their complex with signal peptidase. J Am Chem Soc, 133, 17869-17877. PubMed id: 21999324 DOI: 10.1021/ja207318n
Date:
13-May-11     Release date:   05-Oct-11    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00803  (LEP_ECOLI) -  Signal peptidase I
Seq:
Struc:
324 a.a.
209 a.a.
Protein chain
Pfam   ArchSchema ?
P00803  (LEP_ECOLI) -  Signal peptidase I
Seq:
Struc:
324 a.a.
223 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.3.4.21.89  - Signal peptidase I.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage of N-terminal leader sequences from secreted and periplasmic proteins precursor.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   2 terms 
  Biological process     proteolysis   1 term 
  Biochemical function     serine-type peptidase activity     1 term  

 

 
DOI no: 10.1021/ja207318n J Am Chem Soc 133:17869-17877 (2011)
PubMed id: 21999324  
 
 
Synthesis and characterization of the arylomycin lipoglycopeptide antibiotics and the crystallographic analysis of their complex with signal peptidase.
J.Liu, C.Luo, P.A.Smith, J.K.Chin, M.G.Page, M.Paetzel, F.E.Romesberg.
 
  ABSTRACT  
 
Glycosylation of natural products, including antibiotics, often plays an important role in determining their physical properties and their biological activity, and thus their potential as drug candidates. The arylomycin class of antibiotics inhibits bacterial type I signal peptidase and is comprised of three related series of natural products with a lipopeptide tail attached to a core macrocycle. Previously, we reported the total synthesis of several A series derivatives, which have unmodified core macrocycles, as well as B series derivatives, which have a nitrated macrocycle. We now report the synthesis and biological evaluation of lipoglycopeptide arylomycin variants whose macrocycles are glycosylated with a deoxy-α-mannose substituent, and also in some cases hydroxylated. The synthesis of the derivatives bearing each possible deoxy-α-mannose enantiomer allowed us to assign the absolute stereochemistry of the sugar in the natural product and also to show that while glycosylation does not alter antibacterial activity, it does appear to improve solubility. Crystallographic structural studies of a lipoglycopeptide arylomycin bound to its signal peptidase target reveal the molecular interactions that underlie inhibition and also that the mannose is directed away from the binding site into solvent which suggests that other modifications may be made at the same position to further increase solubility and thus reduce protein binding and possibly optimize the pharmacokinetics of the scaffold.