Orlistat response to missense mutations in lipoprotein lipase.
The human lipoprotein lipase (LPL) is a therapeutic target for obesity, and inhibition of LPL with the approved small molecule agent orlistat has been widely used in clinic to treat obesity-related health problems such as diabetes and cardiovascular diseases. However, a variety of missense mutations in LPL protein have been observed, which may cause resistance or sensitization for orlistat, largely limiting the clinical applications of orlistat in obesity therapy. Here, we integrated molecular dynamics simulations and enzyme inhibition to investigate orlistat response to 16 disorder-associated missense mutations in LPL catalytic domain. It was found that most mutations have a modest effect on orlistat binding, and only few can exert strong impact to the binding. Three unfavorable (Trp86Arg, Ile194Thr, and Glu242Lys) and two favorable (His136Arg and Gly188Glu) mutations were identified, which can alter the binding affinity and inhibitory activity of orlistat considerably. Structural and energetic analysis revealed that these potent mutations induce orlistat resistance and sensitization by directly influencing the intermolecular interaction between LPL and orlistat or by indirectly addressing allosteric effect on LPL structure.
Institute of Life Sciences, Jiangsu University, Zhenjiang, People's Republic of China.|National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, People's Republic of China.|Division of Biological Sciences, University of California at San Diego, La Jolla, CA, USA.
Huayou
H
Chen
Institute of Life Sciences, Jiangsu University, Zhenjiang, People's Republic of China.
Jinru
J
Jia
Institute of Life Sciences, Jiangsu University, Zhenjiang, People's Republic of China.
Zhong
Z
Ni
Division of Biological Sciences, University of California at San Diego, La Jolla, CA, USA.
Ake
A
Vastermark
Institute of Life Sciences, Jiangsu University, Zhenjiang, People's Republic of China.
Bangguo
B
Wu
Institute of Life Sciences, Jiangsu University, Zhenjiang, People's Republic of China.
Yilin
Y
Le
Institute of Life Sciences, Jiangsu University, Zhenjiang, People's Republic of China.
Ullah
U
Jawad
D000494:Allosteric Regulation / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D020125:Mutation, Missense / Q000235:genetics*; D000077403:Orlistat; D013329:Structure-Activity Relationship
D007783:Lactones; D000077403:Orlistat; C548261:LPL protein, human; D008071:Lipoprotein Lipase
lipoprotein lipase; missense mutation; orlistat