6iix

The crystal structure of acyltransferase mutant, orf11*-W163A, in complex with octanoyl-CoA

spinqualitylabelsall models 6iix, resolution 1.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6iix is a 1 chain structure with sequence from Actinoplanes teichomyceticus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.73Å Ligands: CO8, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q70AY4_ACTTI Publication Abstract from PubMed Lipoglycopeptide antibiotics, for example, teicoplanin (Tei) and A40926, are more potent than vancomycin against Gram-positive (Gram-(+)) drug-resistant pathogens, for example, methicillin-resistant Staphylococcus aureus (MRSA). To extend their therapeutic effectiveness on vancomycin-resistant S. aureus (VRSA), the biosynthetic pathway of the N-acyl glucosamine (Glc) pharmacophore at residue 4 (r4) of teicoplanin pseudoaglycone redirection to residue 6 (r6) was attempted. On the basis of crystal structures, two regioselective biocatalysts Orf2*T (a triple-mutation mutant S98A/V121A/F193Y) and Orf11*S (a single-mutation mutant W163A) were engineered, allowing them to act on GlcNAc at r6. New analogs thereby made show marked antimicrobial activity against MRSA and VRSA by 2-3 orders of magnitude better than teicoplanin and vancomycin. The lipid side chain of the Tei-analogs armed with a terminal mono- or diguanidino group extends the antimicrobial specificity from Gram-(+) to Gram-negative (Gram-(-)), comparable to that of kanamycin. In addition to low cytotoxicity and high safety, the Tei analogs exhibit new modes of action as a result of resensitization of VRSA and Acinetobacter baumannii. The redirection of the biosynthetic pathway for the N-acyl-Glc pharmacophore from r4 to r6 bodes well for large-scale production of selected r6,Tei congeners in an environmentally friendly synthetic biology approach. Teicoplanin Reprogrammed with the N-Acyl-Glucosamine Pharmacophore at the Penultimate Residue of Aglycone Acquires Broad-Spectrum Antimicrobial Activities Effectively Killing Gram-Positive and -Negative Pathogens.,Huang CM, Lyu SY, Lin KH, Chen CL, Chen MH, Shih HW, Hsu NS, Lo IW, Wang YL, Li YS, Wu CJ, Li TL ACS Infect Dis. 2019 Mar 8;5(3):430-442. doi: 10.1021/acsinfecdis.8b00317. Epub, 2019 Jan 11. PMID:30599088 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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