4MFP: The Crystal Structure Of Acyltransferase In Complex With Decanoyl-coa And Tei Pseudoaglycone

Citation:
Abstract
Teicoplanin A2-2 (Tei)/A40926 is the last-line antibiotic to treat multidrug-resistant Gram-positive bacterial infections, e.g., methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). This class of antibiotics is powered by the N-acyltransferase (NAT) Orf11*/Dbv8 through N-acylation on glucosamine at the central residue of Tei/A40926 pseudoaglycone. The NAT enzyme possesses enormous value in untapped applications; its advanced development is hampered largely due to a lack of structural information. In this report, we present eight high-resolution X-ray crystallographic unary, binary, and ternary complexes in order to decipher the molecular basis for NAT's functionality. The enzyme undergoes a multistage conformational change upon binding of acyl-CoA, thus allowing the uploading of Tei pseudoaglycone to enable the acyl-transfer reaction to take place in the occlusion between the N- and C-halves of the protein. The acyl moiety of acyl-CoA can be bulky or lengthy, allowing a large extent of diversity in new derivatives that can be formed upon its transfer. Vancomycin/synthetic acyl-N-acetyl cysteamine was not expected to be able to serve as a surrogate for an acyl acceptor/donor, respectively. Most strikingly, NAT can catalyze formation of 2-N,6-O-diacylated or C6-->C2 acyl-substituted Tei analogues through an unusual 1,4-migration mechanism under stoichiometric/solvational reaction control, wherein selected representatives showed excellent biological activities, effectively counteracting major types (VanABC) of VRE.
PDB ID: 4MFPDownload
MMDB ID: 122843
PDB Deposition Date: 2013/8/28
Updated in MMDB: 2014/09
Experimental Method:
x-ray diffraction
Resolution: 2.15  Å
Source Organism:
Similar Structures:
Biological Unit for 4MFP: dimeric; determined by author
Molecular Components in 4MFP
Label Count Molecule
Protein (1 molecule)
1
Putative Uncharacterized Protein Tcp24
Molecule annotation
Nucleotide(1 molecule)
1
Teicoplanin Pseudoaglycone
Molecule annotation
Chemicals (7 molecules)
1
1
2
2
3
1
4
1
5
1
6
1
* Click molecule labels to explore molecular sequence information.

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