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|3nxq, resolution 1.99Å ()|
|Ligands:||, , , , , , , ,|
|Gene:||ACE, DCP, DCP1 (Homo sapiens)|
Angiotensin Converting Enzyme N domain glycsoylation mutant (Ndom389) in complex with RXP407
ACE plays a critical role in the regulation of blood pressure through its central role in the renin-angiotensin and kallikrein-kinin systems. ACE contains two domains, the N and C domains, both of which are heavily glycosylated. Structural studies of ACE have been fraught with severe difficulties because of surface glycosylation of the protein. In order to investigate the role of glycosylation in the N domain and to create suitable forms for crystallization, we have investigated the importance of the ten potential N-linked glycan sites using enzymatic deglycosylation, limited proteolysis and mass spectrometry. A number of glycosylation mutants were generated via site-directed mutagenesis, expressed in CHO cells and analysed for enzymatic activity and thermal stability. At least seven out of ten of the potential glycan sites are glycosylated; three C-terminal sites were sufficient for expression of active N domain while two N-terminal sites are important for its thermal stability. The minimally glycosylated Ndom389 construct was highly suitable for crystallization studies. The structure in the presence of an N domain selective phosphinic inhibitor RXP407 was determined to 2.0 resolution. The Ndom389 structure revealed a hinge region that may contribute to the breathing motion proposed for substrate binding.
The N domain of human angiotensin-I converting enzyme: the role of N-glycosylation and the crystal structure in complex with an N domain specific phosphinic inhibitor RXP407., Anthony CS, Corradi HR, Schwager SL, Redelinghuys P, Georgiadis D, Dive V, Acharya KR, Sturrock ED, J Biol Chem. 2010 Sep 8. PMID:20826823
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[ACE_HUMAN] Genetic variations in ACE may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Defects in ACE are a cause of renal tubular dysgenesis (RTD) [MIM:267430]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). Genetic variations in ACE are associated with susceptibility to microvascular complications of diabetes type 3 (MVCD3) [MIM:612624]. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Defects in ACE are a cause of susceptibility to intracerebral hemorrhage (ICH) [MIM:614519]. A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke.
[ACE_HUMAN] Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety.
About this Structure
- Anthony CS, Corradi HR, Schwager SL, Redelinghuys P, Georgiadis D, Dive V, Acharya KR, Sturrock ED. The N domain of human angiotensin-I converting enzyme: the role of N-glycosylation and the crystal structure in complex with an N domain specific phosphinic inhibitor RXP407. J Biol Chem. 2010 Sep 8. PMID:20826823 doi:10.1074/jbc.M110.167866
- ↑ Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004 Nov;61(11):1652-61. PMID:15534175 doi:61/11/1652
- ↑ Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623
- ↑ Slowik A, Turaj W, Dziedzic T, Haefele A, Pera J, Malecki MT, Glodzik-Sobanska L, Szermer P, Figlewicz DA, Szczudlik A. DD genotype of ACE gene is a risk factor for intracerebral hemorrhage. Neurology. 2004 Jul 27;63(2):359-61. PMID:15277638