7lex
Trimeric human Arginase 1 in complex with mAb1 - 2 hArg:3 mAb1 complex
Structural highlights
DiseaseARGI1_HUMAN Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:207800; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.[1] [2] FunctionPublication Abstract from PubMedHuman 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 A 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. Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action.,Palte RL, Juan V, Gomez-Llorente Y, Bailly MA, Chakravarthy K, Chen X, Cipriano D, Fayad GN, Fayadat-Dilman L, Gathiaka S, Greb H, Hall B, Handa M, Hsieh M, Kofman E, Lin H, Miller JR, Nguyen N, O'Neil J, Shaheen H, Sterner E, Strickland C, Sun A, Taremi S, Scapin G Commun Biol. 2021 Jul 29;4(1):927. doi: 10.1038/s42003-021-02444-z. PMID:34326456[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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