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Structural Research of O-acyltransferases

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Membrane-bound O-acyltransferase (MBOAT) is involved in neutral lipid biosynthesis, protein/peptide acylation, and phospholipid remodeling. The members of this family all contain multiple transmembrane domains, and most carry two conserved residues, one conserved histidine (His) embedded in a hydrophobic residue segment and one asparagine (Asn) or histidine located in a more hydrophilic upstream region. Some MBOAT members are drug targets for human diseases, including atherosclerosis, obesity, Alzheimer's disease, and viral infection.

Structural research on the bacterial DltB protein

The structure of DltB, an MBOAT protein from Streptococcus thermophilus (Q5M4V4), has been investigated at 3.3 Å resolution. DltB is essential for D-alanylation of bacterial cell wall phosphomimetic acids. It contains 415 amino acid residues, with both the N- and C-termini located extracellularly. It forms 17 helices located mainly within the lipid bilayer. Of these, 11 transmembrane helices form an external circular ridge and shield the thinner central region. This region is the core site involved in catalysis.

Action mechanism of DltB protein

There is an approximately straight tunnel between the bottom of the extracellular funnel and the cytoplasmic side. The tunnel is formed by three DltB spirals (H13-H15) and a horizontal spiral H12 at the center core. The residues in the tunnel are highly conserved in the DltB protein. This tunnel is connected to partner DltC, which carries D-alanine to the bottom of the funnel for catalytic reactions.

The overall structure of DltB. Figure 1. The overall structure of DltB. (Ma D, et al., 2018)

Protein Organism Method Resolution PDB Entry ID
A membrane protein, crystal form I Streptococcus thermophilus X-ray diffraction 3.27 Å 6BUG
A membrane protein, crystal form II Streptococcus thermophilus X-ray diffraction 3.15 Å 6BUH
A membrane protein, crystal form III Streptococcus thermophilus X-ray diffraction 3.27 Å 6BUI
Diacylglycerol Acyltransferase 1 in complex with oleoyl-CoA Homo sapiens Cryo-EM single particle analysis 3.1 Å 6VP0
Sterol O-acyltransferase 1 in complex with CI-976 Homo sapiens Cryo-EM single particle analysis 3.5 Å 6L47
Sterol O-acyltransferase 1 in resting state Homo sapiens Cryo-EM single particle analysis 3.5 Å 6L48
Dimeric of ACAT1 Homo sapiens Cryo-EM single particle analysis 3 Å 6P2J
Tetrameric of ACAT1 Homo sapiens Cryo-EM single particle analysis 3.1 Å 6P2P
Nevanimibe bound ACAT2 Homo sapiens Cryo-EM single particle analysis 3.93 Å 7N6R
Triacylglycerol synthesizing enzyme DGAT1 in complex with T863 inhibitor Homo sapiens Cryo-EM single particle analysis 3.2 Å 8ESM
Triacylglycerol synthesizing enzyme DGAT1 in complex with DGAT1IN1 inhibitor Homo sapiens Cryo-EM single particle analysis 3.2 Å 8ETM
Diacylglycerol O-acyltransferase 1 Homo sapiens Cryo-EM single particle analysis 3 Å 6VYI
Diacylglycerol O-acyltransferase 1 complexed with acyl-CoA substrate Homo sapiens Cryo-EM single particle analysis 3.2 Å 6VZI
Nevanimibe-bound tetrameric ACAT1 Homo sapiens Cryo-EM single particle analysis 3.67 Å 6VUM
PPPA boundACAT2 Homo sapiens Cryo-EM single particle analysis 3.87 Å 7N6Q
Hedgehog acyltransferase (HHAT) in complex with palmitoyl-CoA and two Fab antibody fragments Homo sapiens Cryo-EM single particle analysis 2.7 Å 7MHY
Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to non-hydrolysable palmitoyl-CoA (Composite Map) Homo sapiens Cryo-EM single particle analysis 2.7 Å 7Q1U
Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to IMP-1575 Homo sapiens Cryo-EM single particle analysis 3.59 Å 7Q6Z
PORCN in complex with Palmitoleoyl-CoA Homo sapiens Cryo-EM single particle analysis 3.11 Å 7URA
PORCN in complex with LGK974 Homo sapiens Cryo-EM single particle analysis 3.14 Å 7URC
PORCN in complex with palmitoleoylated WNT3A peptide Homo sapiens Cryo-EM single particle analysis 3.19 Å 7URE
PORCN in complex with LGK974 and WNT3A peptide Homo sapiens Cryo-EM single particle analysis 2.92 Å 7URD
Lysophospholipid acyltransferase LPCAT3 (MOBAT5) in its monomeric and apo form Gallus gallus X-ray diffraction 3.4 Å 7EWT
Lysophospholipid acyltransferase LPCAT3 in complex with lysophosphatidylcholine Gallus gallus Cryo-EM single particle analysis 3.57 Å 7F3X
Brassica napus DGAT1 exosite Brassica napus SOLUTION NMR / 5UZL

Table 1. Structural research of membrane-bound O-acyltransferase (MBOAT).

Creative Biostructure has long been committed to the study of structural biology and membrane proteins. We have extensive experience in determining membrane protein structures using NMR spectroscopy, cryo-electron microscopy (cryo-EM) and X-ray crystallography. Studying the structure of MBOAT family proteins is beneficial for the development of antibacterial agents and the investigation of drug targets for human diseases.

In addition to the structural determination of membrane proteins, we can accurately analyze biomolecules, including but not limited to nucleic acids, ribosomes, small proteins, protein complexes, protein-ligand complexes, and viruses. If you are interested in our services, please contact us for more details.

References

  1. Ma D, et al. Crystal structure of a membrane-bound O-acyltransferase. Nature. 2018. 562(7726):286-290.
  2. Chang, et al. Membrane-bound O-acyltransferases (MBOATs). Frontiers in Biology 6. 2011:177-182.

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