Sandbox 51: Difference between revisions

The inhibition of pancreatic lipase has serious effects on storage and absorption of fats taken in by the body, and is therefore a potentially strong basis for pharmaceuticals to combat obesity.  Because lipase is a part of the serine esterase family, it is inhibited in a similar manner.  One such compound is a <scene name='Sandbox_51/Inhibitor/2'>C11 alkyl phosphonate</scene> inhibitor (shown interacting with the lipase-coplipase structure).  The inhibitor acts by binding <scene name='Sandbox_51/Inhibitor_at_ser152/2'>Ser152</scene> in the active site inducing conformational changes in the beta-5 loop structures.  The alkyl chain fits into the hydrophobic portion of the active lipase-colipase complex mimicking the fatty acid produced through hydrolysis in the normal enzymatic reaction <ref>Egloff, M.P., etc. "The 2.46 angstroms resolution structure of the pancreatic lipase colipase complex inhibited by a C11 alkyl phosphonate."(1995) J. Biochemistry 34: 2751-2762 [http://www.pdb.org/pdb/explore/explore.do?structureId=1lpb]</ref>.  Van der waals forces between hydrophobic residues (blue) in the groove stabilize C11P binding, in addition to salt bridging and Hydrogen bonding forces with a cluster of hydrophilic residues (pick)  around the Ser152 residue (purple) in the <scene name='Sandbox_51/Inhibitor_pocket/2'>inhibitor binding groove</scene>. <ref>Egloff, M., Marguet, F., Buono, G.,Verger,R.,Cambillau,C., Tilbeurgho,H. The 2.46 A Resolution Structure of the Pancreatic Lipase-Colipase Complex