Crystal structure of a membrane-bound O-acyltransferase
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View abstract on PubMed
Summary
This summary is machine-generated.Crystal structures reveal the molecular architecture of DltB, a membrane-bound O-acyltransferase (MBOAT) involved in bacterial cell-wall modification. These findings elucidate MBOAT mechanisms and offer a basis for developing new therapeutic inhibitors.
Area Of Science
- Biochemistry
- Structural Biology
- Microbiology
Background
- Membrane-bound O-acyltransferases (MBOATs) are crucial integral transmembrane enzymes across all life forms.
- MBOATs play vital roles in lipid biosynthesis, phospholipid remodeling, and lipid modification of secreted proteins.
- Despite their importance as drug targets, the molecular architecture and mechanisms of MBOATs remain largely uncharacterized.
Purpose Of The Study
- To determine the crystal structures of DltB, a bacterial MBOAT, alone and complexed with its D-alanyl donor protein DltC.
- To elucidate the molecular architecture and functional mechanism of DltB, particularly its role in D-alanylation of cell-wall teichoic acid.
- To provide insights into the conserved structural core and catalytic mechanisms of MBOATs across different organisms.
Main Methods
- X-ray crystallography was employed to obtain high-resolution structures of DltB and its complex with DltC.
- Site-directed mutagenesis was used to investigate the function of key residues, including the catalytic histidine and DltC-binding site.
- Structure-guided sequence comparisons were performed between bacterial DltB and vertebrate MBOATs.
Main Results
- The crystal structures reveal DltB possesses a ring of 11 transmembrane helices shielding an extracellular funnel leading to a narrow intracellular tunnel.
- A conserved catalytic histidine residue is located at the funnel's base, connected to DltC via the tunnel.
- Mutations in the catalytic histidine or DltC-binding site abolished D-alanylation and sensitized Bacillus subtilis to cell-wall stress, indicating cross-membrane catalysis.
Conclusions
- The determined structures provide unprecedented insights into the molecular architecture and mechanism of MBOATs.
- The findings suggest a conserved structural core and similar catalytic mechanisms across MBOATs from diverse organisms.
- These structures serve as a template for understanding MBOAT structure-function relationships and for the rational design of MBOAT inhibitors.
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