Structure of lipoprotein lipase in complex with GPIHBP1

Significance LPL is the central enzyme in TG metabolism. We report here X-ray crystal structures of LPL in complex with its accessory protein GPIHBP1, including a structure with a novel inhibitor bound in the LPL active site. The inhibitor-bound structure includes the LPL lid and lipid-binding regions, which makes this the first complete crystal structure of LPL and provides insight into how these regions of LPL contribute to the recognition of TRL substrates. The structural evidence and additional biochemical experiments presented here are consistent with a newly published report that LPL, in complex with GPIHBP1, can be active as a monomeric 1:1 complex and, therefore, help overturn the long-standing assumption that LPL is only active as a homodimer.