2aeb
From Proteopedia
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| , resolution 1.29Å | |||||||
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| Ligands: | , | ||||||
| Activity: | Arginase, with EC number 3.5.3.1 | ||||||
| Related: | 1vwa, 1D3V
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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 Mon Mar 31 01:51:27 2008
