STRUCTURAL STUDIES ON HUMAN MUSCLE FATTY-ACID-BINDING PROTEIN AT 1.4-ANGSTROM RESOLUTION - BINDING INTERACTIONS WITH 3 C18 FATTY-ACIDS

Background: Muscle fatty acid binding protein (M-FABP) is one of a fam ily of cytosolic lipid-binding proteins involved in fatty acid process ing. In order to investigate the precise interactions between M-FABP a nd its ligands and to understand the structural basis of differential binding affinity, we have compared the structures of M-FABP in complex with three C18 fatty acids. Results: We describe the crystal structur es of M-FABP in complex with n-octadecanoate (stearate), trans Delta(9 )-octadecenoate (elaidate) and cis-Delta(9)-octadecenoate (oleate). Th ese structures were refined using least-squares positional and anisotr opic temperature factor refinement to final R-factors of 11.4 %, 12.1 % and 13.2 % respectively for all the data between 8.0 Angstrom and 1. 4 Angstrom resolution. Conclusions: Stearate, elaidate and oleate each adopt highly similar U-shaped conformations when they bind to M-FABP within a large interior binding cavity, which also contains 13 ordered water molecules. The atomic structure of the protein is virtually ide ntical, regardless of the nature of the bound ligand. The fatty acid i s thought to enter the interior cavity of the protein via a portal in its surface while interior solvent is released through a secondary ope ning. The ligand affinity can be correlated with the conformational en ergy and the solubility of the bound ligand.