3nxq: Difference between revisions
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==Angiotensin Converting Enzyme N domain glycsoylation mutant (Ndom389) in complex with RXP407== | ==Angiotensin Converting Enzyme N domain glycsoylation mutant (Ndom389) in complex with RXP407== | ||
<StructureSection load='3nxq' size='340' side='right' caption='[[3nxq]], [[Resolution|resolution]] 1.99Å' scene=''> | <StructureSection load='3nxq' size='340' side='right'caption='[[3nxq]], [[Resolution|resolution]] 1.99Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3nxq]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3nxq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NXQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NXQ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=RX4:N~2~-ACETYL-N-{(1R)-1-[(S)-[(2S)-3-{[(2S)-1-AMINO-1-OXOPROPAN-2-YL]AMINO}-2-METHYL-3-OXOPROPYL](HYDROXY)PHOSPHORYL]-2-PHENYLETHYL}-L-ALPHA-ASPARAGINE'>RX4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=RX4:N~2~-ACETYL-N-{(1R)-1-[(S)-[(2S)-3-{[(2S)-1-AMINO-1-OXOPROPAN-2-YL]AMINO}-2-METHYL-3-OXOPROPYL](HYDROXY)PHOSPHORYL]-2-PHENYLETHYL}-L-ALPHA-ASPARAGINE'>RX4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3nxq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nxq OCA], [https://pdbe.org/3nxq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nxq RCSB], [https://www.ebi.ac.uk/pdbsum/3nxq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nxq ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/ACE_HUMAN ACE_HUMAN] Genetic variations in ACE may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:[https://omim.org/entry/601367 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.<ref>PMID:15534175</ref> Defects in ACE are a cause of renal tubular dysgenesis (RTD) [MIM:[https://omim.org/entry/267430 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).<ref>PMID:16116425</ref> Genetic variations in ACE are associated with susceptibility to microvascular complications of diabetes type 3 (MVCD3) [MIM:[https://omim.org/entry/612624 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:[https://omim.org/entry/614519 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.<ref>PMID:15277638</ref> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/ACE_HUMAN 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. | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nx/3nxq_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nx/3nxq_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/ | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
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==See Also== | ==See Also== | ||
*[[Angiotensin-Converting Enzyme|Angiotensin-Converting Enzyme]] | *[[Angiotensin-Converting Enzyme 3D structures|Angiotensin-Converting Enzyme 3D structures]] | ||
*[[Carboxypeptidase|Carboxypeptidase]] | *[[Carboxypeptidase 3D structures|Carboxypeptidase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Acharya | [[Category: Large Structures]] | ||
[[Category: Anthony | [[Category: Acharya KR]] | ||
[[Category: Corradi | [[Category: Anthony CS]] | ||
[[Category: Dive | [[Category: Corradi HR]] | ||
[[Category: Georgiadis | [[Category: Dive V]] | ||
[[Category: Redelinghuys | [[Category: Georgiadis D]] | ||
[[Category: Schwager | [[Category: Redelinghuys P]] | ||
[[Category: Sturrock | [[Category: Schwager SLU]] | ||
[[Category: Sturrock ED]] | |||
Latest revision as of 09:01, 17 October 2024
Angiotensin Converting Enzyme N domain glycsoylation mutant (Ndom389) in complex with RXP407Angiotensin Converting Enzyme N domain glycsoylation mutant (Ndom389) in complex with RXP407
Structural highlights
DiseaseACE_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.[1] 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).[2] 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.[3] FunctionACE_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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedACE 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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