2gcg

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spinqualitylabelsall models 2gcg, resolution 2.200Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Ternary Crystal Structure of Human Glyoxylate Reductase/Hydroxypyruvate Reductase

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Human glyoxylate reductase/hydroxypyruvate reductase (GRHPR) is a, D-2-hydroxy-acid dehydrogenase that plays a critical role in the removal, of the metabolic by-product glyoxylate from within the liver. Deficiency, of this enzyme is the underlying cause of primary hyperoxaluria type 2, (PH2) and leads to increased urinary oxalate levels, formation of kidney, stones and renal failure. Here we describe the crystal structure of human, GRHPR at 2.2 A resolution. There are four copies of GRHPR in the, crystallographic asymmetric unit: in each homodimer, one subunit forms a, ternary (enzyme+NADPH+reduced substrate) complex, and the other a binary, (enzyme+NADPH) form. The spatial arrangement of the two enzyme domains is, the same in binary and ternary forms. This first crystal structure of a, true ternary complex of an enzyme from this family demonstrates the, relationship of substrate and catalytic residues within the active site, confirming earlier proposals of the mode of substrate binding, stereospecificity and likely catalytic mechanism for these enzymes. GRHPR, has an unusual substrate specificity, preferring glyoxylate and, hydroxypyruvate, but not pyruvate. A tryptophan residue (Trp141) from the, neighbouring subunit of the dimer is projected into the active site region, and appears to contribute to the selectivity for hydroxypyruvate. This, first crystal structure of a human GRHPR enzyme also explains the, deleterious effects of naturally occurring missense mutations of this, enzyme that lead to PH2.

Disease

Known diseases associated with this structure: Hyperoxaluria, primary, type II OMIM:[604296]

About this Structure

2GCG is a Single protein structure of sequence from Homo sapiens with SO4, NDP and DGY as ligands. Active as Glyoxylate reductase (NADP(+)), with EC number 1.1.1.79 Full crystallographic information is available from OCA.

Reference

Structural basis of substrate specificity in human glyoxylate reductase/hydroxypyruvate reductase., Booth MP, Conners R, Rumsby G, Brady RL, J Mol Biol. 2006 Jun 30;360(1):178-89. Epub 2006 May 22. PMID:16756993

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