7SH0

CRYSTAL STRUCTURE OF ENDOPLASMIC RETICULUM AMINOPEPTIDASE 2 (ERAP2) COMPLEX WITH A HIGHLY SELECTIVE AND POTENT SMALL MOLECULE

Summary for 7SH0

• Entry DOI: 10.2210/pdb7sh0/pdb
• Descriptor: Endoplasmic reticulum aminopeptidase 2, ZINC ION, (2S)-N-hydroxy-3-(4-methoxyphenyl)-2-[4-({[5-(pyridin-2-yl)thiophene-2-sulfonyl]amino}methyl)-1H-1,2,3-triazol-1-yl]propanamide, ... (7 entities in total)
• Functional Keywords: aminopeptidase, erap2 structure, enzyme inhibitor, antigen processing, immune system, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 225329.06

Authors

Li, L.,Bouvier, M. (deposition date: 2021-10-07, release date: 2022-07-20, Last modification date: 2024-11-13)

Primary citation

Camberlein, V.,Fleau, C.,Sierocki, P.,Li, L.,Gealageas, R.,Bosc, D.,Guillaume, V.,Warenghem, S.,Leroux, F.,Rosell, M.,Cheng, K.,Medve, L.,Prigent, M.,Decanter, M.,Piveteau, C.,Biela, A.,Eveque, M.,Dumont, J.,Mpakali, A.,Giastas, P.,Herledan, A.,Couturier, C.,Haupenthal, J.,Lesire, L.,Hirsch, A.K.H.,Deprez, B.,Stratikos, E.,Bouvier, M.,Deprez-Poulain, R.
Discovery of the First Selective Nanomolar Inhibitors of ERAP2 by Kinetic Target-Guided Synthesis.
Angew.Chem.Int.Ed.Engl., 61:e202203560-e202203560, 2022

PubMed Abstract: Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a key enzyme involved in the trimming of antigenic peptides presented by Major Histocompatibility Complex class I. It is a target of growing interest for the treatment of autoimmune diseases and in cancer immunotherapy. However, the discovery of potent and selective ERAP2 inhibitors is highly challenging. Herein, we have used kinetic target-guided synthesis (KTGS) to identify such inhibitors. Co-crystallization experiments revealed the binding mode of three different inhibitors with increasing potency and selectivity over related enzymes. Selected analogues engage ERAP2 in cells and inhibit antigen presentation in a cellular context. 4 d (BDM88951) displays favorable in vitro ADME properties and in vivo exposure. In summary, KTGS allowed the discovery of the first nanomolar and selective highly promising ERAP2 inhibitors that pave the way of the exploration of the biological roles of this enzyme and provide lead compounds for drug discovery efforts.

PubMed: 35904863
DOI: 10.1002/anie.202203560

Experimental method

X-RAY DIFFRACTION (3.2 Å)