Cartilage oligomerization matrix protein is a noncollagenous glycoprotein of the thrombospondin family that is found in cartilage, tendons, and ligaments. It is a homopentamer consisting of five subunits held together by interchain disulfide bridges in the N-terminal coiled-coil domain composed of residues 27–72. The COMPcc chain fragment forms a parallel left-handed coiled-coil with an average length of 70 A˚ and an average outer diameter of about 30 A˚. The axial pore of the pentamer is divided by the hydrophilic Gln54 ring system into two hydrophobic cavities that are exclusively lined with aliphatic side chains. According to the heptad repeat pattern of left-handed coiled coils, residues in a positions of COMPcc form perpendicular knobs-into holes, whereas residues in d position are oriented in a parallel manner. The binding of a number of biologically relevant hydrophobic compounds to recombinantly expressed COMPcc has been shown, with crystal structures available for the COMPcc-vitamin D3, COMPcc-all-trans retinol, and COMPcc-benzene complexes. The binding properties of the hydrophobic channel suggest the potential of COMPcc to be used as a storage and delivery system for hydrophobic compounds. Fatty acids have diverse and important biological functions in cells. They are involved in protein acylation, transcription regulation, apoptosis, energy production and storage, and membrane synthesis. They are essential key components in numerous signaling cascades involving TLR and insulin signaling as well as inflammatory responses. FA’s comprise approximately 30–40% of total fatty acids in animal tissues, with the majority being palmitic acid, followed by stearic acid, myristic acid, and lauric acid. Natural receptors for FA’s include family members of the albumin and fatty acid-binding protein family. These proteins serve to Regorafenib increase the solubility of fatty acids and mediate their transport within cells. While there are many members of the FABP family with a great deal of variance in protein sequence, all members share a common ß-barrel structural motif. The 10- stranded antiparallel ß-barrel contains a hydrophobic core to which fatty acids bind. The core is capped on one end by an Nterminal helix-turn-helix motif. Inside the binding pocket, the carboxyl group is coordinated through electrostatic interactions with tyrosine and two arginine residues. The hydrocarbon tail is oriented with hydrophobic residues on one side and ordered water molecules on the other side. Multiple fatty acid binding sites have been shown for Human Serum Albumin revealing a combined contribution of electrostatic and hydrophobic forces to the binding interactions. Interestingly, the carboxylate head group of the bound fatty acids are more tightly bound than their methylene tail. In the current work, we have solved the crystal structures of COMPcc in complex with myristic acid, palmitic acid, stearic acid and oleic acid. In addition, the binding of these ligands to COMPcc in solution has also been studied with fluorescence spectroscopy. From the binding constants we have deciphered a trend in binding favorability that is determined by length of the aliphatic tail and geometry altered by introduction of a cis-configured double bond. A significant finding of this study is the observation that only fatty acids in an elongated configuration can pass the selectivity filter formed by the ring of five Met33 residues located at the entrance to the hydrophobic channel.