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Photochemical probe identification of the small-molecule binding site in a mammalian membrane-bound O-acyltransferase
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.10.16.342477v1?rss=1
Authors: Lanyon-Hogg, T., Ritzefeld, M., Zhang, L., Pogranyi, B., Mondal, M., Johnston, C. D., Coupland, C. E., Sefer, L., Andrei, S. A., Newington, J., Magee, A. I., Siebold, C., Tate, E. W.
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 development of a photochemical probe to interrogate the small-molecule binding site in the human MBOAT Hedgehog acyltransferase (HHAT) based on HHAT inhibitor RUSKI-201. Structure-activity relationship investigation identified the improved enantiomeric inhibitor IMP 1575, which is the most potent HHAT inhibitor reported to-date, and guided rational design of a photocrosslinking probe 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 via kinetic analysis. Our results provide an optimal HHAT inhibitor IMP-1575 (Ki = 38 nM) and a strategy for mapping of interaction sites in MBOATs.
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By Multimodal LLCLink to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.10.16.342477v1?rss=1
Authors: Lanyon-Hogg, T., Ritzefeld, M., Zhang, L., Pogranyi, B., Mondal, M., Johnston, C. D., Coupland, C. E., Sefer, L., Andrei, S. A., Newington, J., Magee, A. I., Siebold, C., Tate, E. W.
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 development of a photochemical probe to interrogate the small-molecule binding site in the human MBOAT Hedgehog acyltransferase (HHAT) based on HHAT inhibitor RUSKI-201. Structure-activity relationship investigation identified the improved enantiomeric inhibitor IMP 1575, which is the most potent HHAT inhibitor reported to-date, and guided rational design of a photocrosslinking probe 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 via kinetic analysis. Our results provide an optimal HHAT inhibitor IMP-1575 (Ki = 38 nM) and a strategy for mapping of interaction sites in MBOATs.
Copy rights belong to original authors. Visit the link for more info