6RD0

Human MMP12 catalytic domain in complex with AP280

Summary for 6RD0

• Entry DOI: 10.2210/pdb6rd0/pdb
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: mmp12, inhibitors, catalytic domain, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18253.12

Authors

Calderone, V.,Fragai, M.,Luchinat, C. (deposition date: 2019-04-12, release date: 2020-02-19, Last modification date: 2024-01-24)

Primary citation

Tsoukalidou, S.,Kakou, M.,Mavridis, I.,Koumantou, D.,Calderone, V.,Fragai, M.,Stratikos, E.,Papakyriakou, A.,Vourloumis, D.
Exploration of zinc-binding groups for the design of inhibitors for the oxytocinase subfamily of M1 aminopeptidases.
Bioorg.Med.Chem., 27:115177-115177, 2019

PubMed Abstract: The oxytocinase subfamily of M1 aminopeptidases consists of three members, ERAP1, ERAP2 and IRAP that play several important biological roles, including key functions in the generation of antigenic peptides that drive human immune responses. They represent emerging targets for pharmacological manipulation of the immune system, albeit lack of selective inhibitors is hampering these efforts. Most of the previously explored small-molecule binders target the active site of the enzymes via strong interactions with the catalytic zinc(II) atom and, while achieving increased potency, they suffer in selectivity. Continuing our earlier efforts on weaker zinc(II) binding groups (ZBG), like the 3,4-diaminobenzoic acid derivatives (DABA), we herein synthesized and biochemically evaluated analogues of nine potentially weak ZBGs, based on differential substitutions of functionalized pyridinone- and pyridinethione-scaffolds, nicotinic-, isonicotinic-, aminobenzoic- and hydrazinobenzoic-acids. Crystallographic analysis of two analogues in complex with a metalloprotease (MMP-12) revealed unexpected binding topologies, consistent with the observed affinities. Our results suggest that the potency of the compounds as inhibitors of ERAP1, ERAP2 and IRAP is primarily driven by the occupation of active-site specificity pockets and their proper orientation within the enzymes.

PubMed: 31711716
DOI: 10.1016/j.bmc.2019.115177

Experimental method

X-RAY DIFFRACTION (1.9 Å)