Carnitine palmitoyltransferase 2: analysis of membrane association and complex structure with a substrate analog.
The mitochondrial membrane-associated carnitine palmitoyltransferase system is a validated target for the treatment of type 2 diabetes mellitus. To further facilitate structure-based drug discovery, we determined the crystal structure of rat CPT-2 (rCPT-2) in complex with the substrate analogue palmitoyl-aminocarnitine at 1.8A resolution. Biochemical analyses revealed a strong effect of this compound on rCPT-2 activity and stability. Using a computational approach we examined the membrane association of rCPT-2. The protein interacts with the membrane as a functional monomer and the calculations confirm the presence of a membrane association domain that consists of layers of hydrophobic and positively charged residues.
Rufer
Arne C
AC
F Hoffmann-La Roche AG, Pharma Research Discovery, Basel, Switzerland.
Lomize
Andrei
A
Benz
Jörg
J
Chomienne
Odile
O
Thoma
Ralf
R
Hennig
Michael
M
D000818:Animals; D001665:Binding Sites; D002331:Carnitine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008958:Models, Molecular; D008962:Models, Theoretical; D011485:Protein Binding; D011489:Protein Denaturation; D051381:Rats; D013379:Substrate Specificity
C511293:ST1326; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine