Inhibition of membrane-bound DPIV by IPC1755 and sitagliptin. (A) IPC1755 (yellow, orange and blue marking) binds to the central pore binding site 2 nm in front of the active site of DPIV. Consequently, the central pore becomes completely blocked. This is crucial, because, in contrast to soluble DPIV, this pore remains the only substrate and inhibitor access route of the membrane-bound enzyme. In contrast to soluble DPIV, alternative substrate access through the side pore of the protease (not shown) has been postulated to be restricted by other membrane proteins, glycolipid-enriched domains and/or lipid rafts . (A) Sitagliptin (orange) binds directly to the active site of DPIV and is therefore able to inhibit both, membrane-bound and soluble DPIV.