7LEX

Trimeric human Arginase 1 in complex with mAb1 - 2 hArg:3 mAb1 complex

Summary for 7LEX

• Entry DOI: 10.2210/pdb7lex/pdb
• EMDB information: 23293
• Descriptor: Arginase-1, mAb1 heavy chain, mAb1 light chain (3 entities in total)
• Functional Keywords: arginase, metalloenzyme, immune system, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 18
• Total formula weight: 651230.69

Authors

Gomez-Llorente, Y.,Scapin, G.,Palte, R.L. (deposition date: 2021-01-15, release date: 2021-09-01, Last modification date: 2024-11-20)

Primary citation

Palte, R.L.,Juan, V.,Gomez-Llorente, Y.,Bailly, M.A.,Chakravarthy, K.,Chen, X.,Cipriano, D.,Fayadat-Dilman, L.,Gathiaka, S.,Greb, H.,Hall, B.,Handa, M.,Hsieh, M.,Kofman, E.,Lin, H.,Miller, J.R.,Nguyen, N.,O'Neil, J.,Shaheen, H.,Sterner, E.,Strickland, C.,Sun, A.,Taremi, S.,Scapin, G.
Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action.
Commun Biol, 4:927-927, 2021

PubMed Abstract: Human Arginase 1 (hArg1) is a metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea, and modulates T-cell-mediated immune response. Arginase-targeted therapies have been pursued across several disease areas including immunology, oncology, nervous system dysfunction, and cardiovascular dysfunction and diseases. Currently, all published hArg1 inhibitors are small molecules usually less than 350 Da in size. Here we report the cryo-electron microscopy structures of potent and inhibitory anti-hArg antibodies bound to hArg1 which form distinct macromolecular complexes that are greater than 650 kDa. With local resolutions of 3.5 Å or better we unambiguously mapped epitopes and paratopes for all five antibodies and determined that the antibodies act through orthosteric and allosteric mechanisms. These hArg1:antibody complexes present an alternative mechanism to inhibit hArg1 activity and highlight the ability to utilize antibodies as probes in the discovery and development of peptide and small molecule inhibitors for enzymes in general.

PubMed: 34326456
DOI: 10.1038/s42003-021-02444-z

Experimental method

ELECTRON MICROSCOPY (3.6 Å)