4Q38

The crystal structure of acyltransferase in complex with decanoyl-CoA and teicoplanin

Summary for 4Q38

• Entry DOI: 10.2210/pdb4q38/pdb
• Related: 4MFJ 4Q36
• Descriptor: Putative uncharacterized protein tcp24, SULFATE ION, COENZYME A, ... (5 entities in total)
• Functional Keywords: acyltransferase, acyl-coa, transferase
• Biological source: Actinoplanes teichomyceticus
• Total number of polymer chains: 1
• Total formula weight: 39765.51

Authors

Li, T.-L.,Lyu, S.-Y.,Liu, Y.-C.,Chang, C.-Y.,Huang, C.-J. (deposition date: 2014-04-11, release date: 2014-09-10, Last modification date: 2023-11-08)

Primary citation

Lyu, S.Y.,Liu, Y.C.,Chang, C.Y.,Huang, C.J.,Chiu, Y.H.,Huang, C.M.,Hsu, N.S.,Lin, K.H.,Wu, C.J.,Tsai, M.D.,Li, T.L.
Multiple complexes of long aliphatic N-acyltransferases lead to synthesis of 2,6-diacylated/2-acyl-substituted glycopeptide antibiotics, effectively killing vancomycin-resistant enterococcus
J.Am.Chem.Soc., 136:10989-10995, 2014

PubMed 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.

PubMed: 25095906
DOI: 10.1021/ja504125v

Experimental method

X-RAY DIFFRACTION (1.99 Å)