AI Article Synopsis
- The MBOAT superfamily plays vital roles in growth, development, and appetite regulation and is a promising target for drugs aimed at treating cancer and obesity.
- This study introduces a novel photochemical probe that helps identify a new binding site for a small-molecule inhibitor called IMP-1575, which is the most effective known inhibitor of HHAT to date.
- Through techniques like photocrosslinking and proteomic sequencing, the research discovered the first small-molecule binding site in a mammalian MBOAT and proposed a potential mechanism for HHAT inhibition confirmed by kinetic analysis.
Article Abstract
The mammalian membrane-bound O-acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small-molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small-molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure-activity relationship investigation identified single enantiomer IMP-1575, the most potent HHAT inhibitor reported to-date, and guided design of photocrosslinking probes that maintained HHAT-inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small-molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed by kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP-1575 (K =38 nM) and a strategy for mapping small molecule interaction sites in MBOATs.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252026 | PMC |
| http://dx.doi.org/10.1002/anie.202014457 | DOI Listing |
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