6Q92

Crystal structure of human Arginase-1 at pH 7.0 in complex with ABH

Summary for 6Q92

• Entry DOI: 10.2210/pdb6q92/pdb
• Descriptor: Arginase-1, MANGANESE (II) ION, 2(S)-AMINO-6-BORONOHEXANOIC ACID, ... (5 entities in total)
• Functional Keywords: hydrolase inhibitor, borate, manganese cluster, ph-dependent, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 74552.18

Authors

Grobben, Y.,Uitdehaag, J.C.M.,Zaman, G.J.R. (deposition date: 2018-12-17, release date: 2019-12-11, Last modification date: 2024-01-24)

Primary citation

Grobben, Y.,Uitdehaag, J.C.M.,Willemsen-Seegers, N.,Tabak, W.W.A.,de Man, J.,Buijsman, R.C.,Zaman, G.J.R.
Structural insights into human Arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158.
J Struct Biol X, 4:100014-100014, 2020

PubMed Abstract: Arginase-1 is a manganese-dependent metalloenzyme that catalyzes the hydrolysis of L-arginine into L-ornithine and urea. Arginase-1 is abundantly expressed by tumor-infiltrating myeloid cells that promote tumor immunosuppression, which is relieved by inhibition of Arginase-1. We have characterized the potencies of the Arginase-1 reference inhibitors (2)-2-amino-6-boronohexanoic acid (ABH) and -hydroxy-nor-L-arginine (nor-NOHA), and studied their pH-dependence and binding kinetics. To gain a better understanding of the structural changes underlying the high pH optimum of Arginase-1 and its pH-dependent inhibition, we determined the crystal structure of the human Arginase-1/ABH complex at pH 7.0 and 9.0. These structures revealed that at increased pH, the manganese cluster assumes a more symmetrical coordination structure, which presumably contributes to its increase in catalytic activity. Furthermore, we show that binding of ABH involves the presence of a sodium ion close to the manganese cluster. We also studied the investigational new drug CB-1158 (INCB001158). This inhibitor has a low-nanomolar potency at pH 7.4 and increases the thermal stability of Arginase-1 more than ABH and nor-NOHA. Moreover, CB-1158 displays slow association and dissociation kinetics at both pH 9.5 and 7.4, as indicated by surface plasmon resonance. The potent character of CB-1158 is presumably due to its increased rigidity compared to ABH as well as the formation of an additional hydrogen-bond network as observed by resolution of the Arginase-1/CB-1158 crystal structure.

PubMed: 32647818
DOI: 10.1016/j.yjsbx.2019.100014

Experimental method

X-RAY DIFFRACTION (1.5 Å)