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-Structure paper
タイトル | Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action. |
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ジャーナル・号・ページ | Commun Biol, Vol. 4, Issue 1, Page 927, Year 2021 |
掲載日 | 2021年7月29日 |
著者 | Rachel L Palte / Veronica Juan / Yacob Gomez-Llorente / Marc Andre Bailly / Kalyan Chakravarthy / Xun Chen / Daniel Cipriano / Ghassan N Fayad / Laurence Fayadat-Dilman / Symon Gathiaka / Heiko Greb / Brian Hall / Mas Handa / Mark Hsieh / Esther Kofman / Heping Lin / J Richard Miller / Nhung Nguyen / Jennifer O'Neil / Hussam Shaheen / Eric Sterner / Corey Strickland / Angie Sun / Shane Taremi / Giovanna Scapin / |
PubMed 要旨 | 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 ...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. |
リンク | Commun Biol / PubMed:34326456 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.05 - 4.15 Å |
構造データ | EMDB-23293, PDB-7lex: EMDB-23294, PDB-7ley: EMDB-23295, PDB-7lez: EMDB-23296, PDB-7lf0: EMDB-23297, PDB-7lf1: EMDB-23298, PDB-7lf2: |
化合物 | ChemComp-MN: |
由来 |
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キーワード | HYDROLASE/IMMUNE SYSTEM / Arginase / Metalloenzyme / IMMUNE SYSTEM / HYDROLASE-IMMUNE SYSTEM complex |