| Structural highlights
Function
[GLPG_ECOLI] Rhomboid-type serine protease that catalyzes intramembrane proteolysis.[1] [2]
Publication Abstract from PubMed
Rhomboids are intramembrane proteases that use a catalytic dyad of serine and histidine for proteolysis. They are conserved in both prokaryotes and eukaryotes and regulate cellular processes as diverse as intercellular signalling, parasitic invasion of host cells, and mitochondrial morphology. Their widespread biological significance and consequent medical potential provides a strong incentive to understand the mechanism of these unusual enzymes for identification of specific inhibitors. In this study, we describe the structure of Escherichia coli rhomboid GlpG covalently bound to a mechanism-based isocoumarin inhibitor. We identify the position of the oxyanion hole, and the S(1)- and S(2)'-binding subsites of GlpG, which are the key determinants of substrate specificity. The inhibitor-bound structure suggests that subtle structural change is sufficient for catalysis, as opposed to large changes proposed from previous structures of unliganded GlpG. Using bound inhibitor as a template, we present a model for substrate binding at the active site and biochemically test its validity. This study provides a foundation for a structural explanation of rhomboid specificity and mechanism, and for inhibitor design.
The structural basis for catalysis and substrate specificity of a rhomboid protease.,Vinothkumar KR, Strisovsky K, Andreeva A, Christova Y, Verhelst S, Freeman M EMBO J. 2010 Oct 1. PMID:20890268[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wu Z, Yan N, Feng L, Oberstein A, Yan H, Baker RP, Gu L, Jeffrey PD, Urban S, Shi Y. Structural analysis of a rhomboid family intramembrane protease reveals a gating mechanism for substrate entry. Nat Struct Mol Biol. 2006 Dec;13(12):1084-91. Epub 2006 Nov 10. PMID:17099694 doi:10.1038/nsmb1179
- ↑ Maegawa S, Ito K, Akiyama Y. Proteolytic action of GlpG, a rhomboid protease in the Escherichia coli cytoplasmic membrane. Biochemistry. 2005 Oct 18;44(41):13543-52. PMID:16216077 doi:10.1021/bi051363k
- ↑ Vinothkumar KR, Strisovsky K, Andreeva A, Christova Y, Verhelst S, Freeman M. The structural basis for catalysis and substrate specificity of a rhomboid protease. EMBO J. 2010 Oct 1. PMID:20890268 doi:10.1038/emboj.2010.243
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