Crystal Structures of ERAP2 Complexed with Inhibitors Reveal Pharmacophore Requirements for Optimizing Inhibitor Potency.
Endoplasmic reticulum aminopeptidase 2 assists with the generation of antigenic peptides for presentation onto Major Histocompatibility Class I molecules in humans. Recent evidence has suggested that the activity of ERAP2 may contribute to the generation of autoimmunity, thus making ERAP2 a possible pharmacological target for the regulation of adaptive immune responses. To better understand the structural elements of inhibitors that govern their binding affinity to the ERAP2 active site, we cocrystallized ERAP2 with a medium activity 3,4-diaminobenzoic acid inhibitor and a poorly active hydroxamic acid derivative. Comparison of these two crystal structures with a previously solved structure of ERAP2 in complex with a potent phosphinic pseudopeptide inhibitor suggests that engaging the substrate N-terminus recognition properties of the active site is crucial for inhibitor binding even in the absence of a potent zinc-binding group. Proper utilization of all five major pharmacophores is necessary, however, to optimize inhibitor potency.
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Anastasia
A
Mpakali
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Petros
P
Giastas
Univ. Lille, Inserm, Institut Pasteur de Lille , U1177-Drugs & Molecules for Living Systems, F-59000 Lille, France.
Rebecca
R
Deprez-Poulain
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Athanasios
A
Papakyriakou
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Despoina
D
Koumantou
Univ. Lille, Inserm, Institut Pasteur de Lille , U1177-Drugs & Molecules for Living Systems, F-59000 Lille, France.
Ronan
R
Gealageas
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Sofia
S
Tsoukalidou
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Dionisios
D
Vourloumis
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Irene M
IM
Mavridis
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Efstratios
E
Stratikos
National Center for Scientific Research Demokritos , Agia Paraskevi, GR-15310 Athens, Greece.
Emmanuel
E
Saridakis
Aminopeptidase; X-ray crystallography; antigen; inhibitors