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{{STRUCTURE_2c6f|  PDB=2c6f  |  SCENE=  }}
===STRUCTURE OF HUMAN SOMATIC ANGIONTENSIN-I CONVERTING ENZYME N DOMAIN===
{{ABSTRACT_PUBMED_16476442}}


==Disease==
==Structure of human somatic angiontensin-I converting enzyme N domain==
[[http://www.uniprot.org/uniprot/ACE_HUMAN ACE_HUMAN]] Genetic variations in ACE may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:[http://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:[http://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:[http://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:[http://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>  
<StructureSection load='2c6f' size='340' side='right'caption='[[2c6f]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2c6f]] 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=2C6F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C6F FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.01&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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'>[https://proteopedia.org/fgij/fg.htm?mol=2c6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c6f OCA], [https://pdbe.org/2c6f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c6f RCSB], [https://www.ebi.ac.uk/pdbsum/2c6f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c6f ProSAT]</span></td></tr>
</table>
== 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 ==
[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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c6/2c6f_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2c6f ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.


==Function==
Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design.,Corradi HR, Schwager SL, Nchinda AT, Sturrock ED, Acharya KR J Mol Biol. 2006 Mar 31;357(3):964-74. Epub 2006 Jan 31. PMID:16476442<ref>PMID:16476442</ref>
[[http://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.  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[2c6f]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C6F OCA].
</div>
<div class="pdbe-citations 2c6f" style="background-color:#fffaf0;"></div>


==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 ==
==Reference==
<references/>
<ref group="xtra">PMID:016476442</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Peptidyl-dipeptidase A]]
[[Category: Large Structures]]
[[Category: Acharya, K R.]]
[[Category: Acharya KR]]
[[Category: Corradi, H R.]]
[[Category: Corradi HR]]
[[Category: Nichinda, A.]]
[[Category: Nichinda A]]
[[Category: Schwager, S L.U.]]
[[Category: Schwager SLU]]
[[Category: Sturrock, E D.]]
[[Category: Sturrock ED]]
[[Category: Angiotensin]]
[[Category: Angiotensin-i converting enzyme]]
[[Category: Carboxypeptidase]]
[[Category: Glycoprotein]]
[[Category: Hydrolase]]
[[Category: Lisinopril]]
[[Category: Metal-binding]]
[[Category: Metalloprotease]]
[[Category: N domain]]
[[Category: Phosphorylation]]
[[Category: Protease]]
[[Category: Transmembrane]]
[[Category: Zinc metallopeptidase]]

Latest revision as of 17:07, 13 December 2023

Structure of human somatic angiontensin-I converting enzyme N domainStructure of human somatic angiontensin-I converting enzyme N domain

Structural highlights

2c6f is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.01Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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.[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]

Function

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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.

Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design.,Corradi HR, Schwager SL, Nchinda AT, Sturrock ED, Acharya KR J Mol Biol. 2006 Mar 31;357(3):964-74. Epub 2006 Jan 31. PMID:16476442[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. 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
  2. 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
  3. 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
  4. Corradi HR, Schwager SL, Nchinda AT, Sturrock ED, Acharya KR. Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design. J Mol Biol. 2006 Mar 31;357(3):964-74. Epub 2006 Jan 31. PMID:16476442 doi:10.1016/j.jmb.2006.01.048

2c6f, resolution 3.01Å

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