3D52

GOLGI MANNOSIDASE II complex with an N-aryl carbamate derivative of gluco-hydroxyiminolactam

Summary for 3D52

• Entry DOI: 10.2210/pdb3d52/pdb
• Related: 1HTY 1HWW 1HXK 1PS2 1QWN 1QWU 1QX1 1R33 1R34 2ALW 2F7O 2F7P 2F7Q 2F7R 3BUB 3BUD 3BUI 3BUP 3BUQ 3BVT 3BVU 3BVV 3BVW 3BVX 3CV5 3CZN 3CZS 3D4Y 3D4Z 3D50 3D51
• Descriptor: Alpha-mannosidase 2, ZINC ION, (4R)-2-METHYLPENTANE-2,4-DIOL, ... (5 entities in total)
• Functional Keywords: gh38 glycosidase, golgi apparatus, hydrolase, membrane, metal-binding, signal-anchor, transmembrane, zinc
• Biological source: Drosophila melanogaster (Fruit fly)
• Total number of polymer chains: 1
• Total formula weight: 120230.94

Authors

Kuntz, D.A.,Tarling, C.A.,Withers, S.G.,Rose, D.R. (deposition date: 2008-05-15, release date: 2008-08-05, Last modification date: 2024-10-30)

Primary citation

Kuntz, D.A.,Tarling, C.A.,Withers, S.G.,Rose, D.R.
Structural analysis of Golgi alpha-mannosidase II inhibitors identified from a focused glycosidase inhibitor screen.
Biochemistry, 47:10058-10068, 2008

PubMed Abstract: The N-glycosylation pathway is a target for pharmaceutical intervention in a number of pathological conditions including cancer. Golgi alpha-mannosidase II (GMII) is the final glycoside hydrolase in the pathway and has been the target for a number of synthetic efforts aimed at providing more selective and effective inhibitors. Drosophila GMII (dGMII) has been extensively studied due to the ease of obtaining high resolution structural data, allowing the observation of substrate distortion upon binding and after formation of a trapped covalent reaction intermediate. However, attempts to find new inhibitor leads by high-throughput screening of large commercial libraries or through in silico docking were unsuccessful. In this paper we provide a kinetic and structural analysis of five inhibitors derived from a small glycosidase-focused library. Surprisingly, four of these were known inhibitors of beta-glucosidases. X-ray crystallographic analysis of the dGMII:inhibitor complexes highlights the ability of the zinc-containing GMII active site to deform compounds, even ones designed as conformationally restricted transition-state mimics of beta-glucosidases, into binding entities that have inhibitory activity. Although these deformed conformations do not appear to be on the expected conformational itinerary of the enzyme, and are thus not transition-state mimics of GMII, they allow positioning of the three vicinal hydroxyls of the bound gluco-inhibitors into similar locations to those found with mannose-containing substrates, underlining the importance of these hydrogen bonds for binding. Further, these studies show the utility of targeting the acid-base catalyst using appropriately positioned positively charged nitrogen atoms, as well as the challenges associated with aglycon substitutions.

PubMed: 18759458
DOI: 10.1021/bi8010785

Experimental method

X-RAY DIFFRACTION (1.6 Å)