Molecular Modeling of the Three-Dimensional Structure of Human Sphingomyelin Synthase
Sphingomyelin synthase （SMS） produces sphingomyelin and diacylglycerol from ceramide and phosphatidyl- choline. It plays an important role in cell survival and apoptosis, inflammation, and lipid homeostasis, and therefore has been noticed in recent years as a novel potential drug target. In this stu...
Saved in:
| Published in | Chinese journal of chemistry Vol. 29; no. 8; pp. 1567 - 1575 |
|---|---|
| Main Author | |
| Format | Journal Article |
| Language | English |
| Published |
Weinheim
WILEY-VCH Verlag
01.08.2011
WILEY‐VCH Verlag Wiley Subscription Services, Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1001-604X 1614-7065 |
| DOI | 10.1002/cjoc.201180282 |
Cover
| Summary: | Sphingomyelin synthase （SMS） produces sphingomyelin and diacylglycerol from ceramide and phosphatidyl- choline. It plays an important role in cell survival and apoptosis, inflammation, and lipid homeostasis, and therefore has been noticed in recent years as a novel potential drug target. In this study, we combined homology modeling, molecular docking, molecular dynamics simulation, and normal mode analysis to derive a three-dimensional struc- ture of human sphingomyelin synthase （hSMS 1） in complex with sphingomyelin. Our model provides a reasonable explanation on the catalytic mechanism of hSMS 1. It can also explain the high selectivity of hSMS 1 towards phos- phocholine and sphingomyelin as well as some other known experimental results about hSMS1. Moreover, we also derived a complex model of D609, the only known small-molecule inhibitor of hSMS 1 so far. Our hSMS 1 model may serve as a reasonable structural basis for the discovery of more effective small-molecule inhibitors of hSMS 1. |
|---|---|
| Bibliography: | 31-1547/O6 Zhang, ya Lin, Fu Deng, Xiaodonga Wang, Renxiao Ye, Deyong （ a School of Pharmacy, Fudan University, Shanghai 201203, China b State Key Lab of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China） sphingomyelin synthase, molecular modeling, molecular dynamics Sphingomyelin synthase （SMS） produces sphingomyelin and diacylglycerol from ceramide and phosphatidyl- choline. It plays an important role in cell survival and apoptosis, inflammation, and lipid homeostasis, and therefore has been noticed in recent years as a novel potential drug target. In this study, we combined homology modeling, molecular docking, molecular dynamics simulation, and normal mode analysis to derive a three-dimensional struc- ture of human sphingomyelin synthase （hSMS 1） in complex with sphingomyelin. Our model provides a reasonable explanation on the catalytic mechanism of hSMS 1. It can also explain the high selectivity of hSMS 1 towards phos- phocholine and sphingomyelin as well as some other known experimental results about hSMS1. Moreover, we also derived a complex model of D609, the only known small-molecule inhibitor of hSMS 1 so far. Our hSMS 1 model may serve as a reasonable structural basis for the discovery of more effective small-molecule inhibitors of hSMS 1. ArticleID:CJOC201180282 a special research fund for the Doctoral Program of Higher Education from the Chinese Ministry of Education - No. 20090071110054 istex:CE179ABFD732982697F96C9C3B2E8D724A3DEE42 ark:/67375/WNG-QRWQVF8P-1 the National Natural Science Foundation of China - No. 20902013 an open grant from the State Key Laboratory of Bio-organic and Natural Products Chemistry, Chinese Academy of Sciences ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 |
| ISSN: | 1001-604X 1614-7065 |
| DOI: | 10.1002/cjoc.201180282 |