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2aeb
From Proteopedia
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[[Image:2aeb.gif|left|200px]] | [[Image:2aeb.gif|left|200px]] | ||
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'''Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in immune response.''' | '''Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in immune response.''' | ||
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[[Category: Rodriguez, P C.]] | [[Category: Rodriguez, P C.]] | ||
[[Category: Sabio, G.]] | [[Category: Sabio, G.]] | ||
| - | [[Category: | + | [[Category: Binuclear manganese cluster]] |
| - | [[Category: | + | [[Category: Boronic acid inhibitor]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[Category: Perfectly twinned crystal]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 18:56:19 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 15:56, 3 May 2008
Crystal structure of human arginase I at 1.29 A resolution and exploration of inhibition in immune response.
Overview
Human arginase I is a potential target for therapeutic intervention in diseases linked to compromised l-arginine homeostasis. Here, we report high-affinity binding of the reaction coordinate analogue inhibitors 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and S-(2-boronoethyl)-l-cysteine (BEC, Kd = 270 nM) to human arginase I, and we report x-ray crystal structures of the respective enzyme-inhibitor complexes at 1.29- and 1.94-A resolution determined from crystals twinned by hemihedry. The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster and illuminates the structural basis for nanomolar affinity: bidentate inner-sphere boronate-manganese coordination interactions and fully saturated hydrogen bond networks with inhibitor alpha-amino and alpha-carboxylate groups. These interactions are therefore implicated in the stabilization of the transition state for l-arginine hydrolysis. Electron density maps also reveal that active-site residue H141 is protonated as the imidazolium cation. The location of H141 is such that it could function as a general acid to protonate the leaving amino group of l-ornithine during catalysis, and this is a revised mechanistic proposal for arginase. This work serves as a foundation for studying the structural and chemical biology of arginase I in the immune response, and we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells.
About this Structure
2AEB is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response., Di Costanzo L, Sabio G, Mora A, Rodriguez PC, Ochoa AC, Centeno F, Christianson DW, Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13058-63. Epub 2005 Sep 2. PMID:16141327 Page seeded by OCA on Sat May 3 18:56:19 2008
