View source for 6en6


==Crystal structure B of the Angiotensin-1 converting enzyme N-domain in complex with a diprolyl inhibitor.==
<StructureSection load='6en6' size='340' side='right'caption='[[6en6]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6en6]] is a 4 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=6EN6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EN6 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BCN:BICINE'>BCN</scene>, <scene name='pdbligand=BJ2:(2~{S})-1-[(2~{S})-2-[[(1~{S})-1-[(2~{S})-1-[(2~{S})-2-azanyl-4-oxidanyl-4-oxidanylidene-butanoyl]pyrrolidin-2-yl]-2-oxidanyl-2-oxidanylidene-ethyl]amino]propanoyl]pyrrolidine-2-carboxylic+acid'>BJ2</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=XPE:3,6,9,12,15,18,21,24,27-NONAOXANONACOSANE-1,29-DIOL'>XPE</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=6en6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6en6 OCA], [https://pdbe.org/6en6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6en6 RCSB], [https://www.ebi.ac.uk/pdbsum/6en6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6en6 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Angiotensin-I converting enzyme (ACE) is a Zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains non-selectively resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension. ACEi from GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, a diprolyl chemical series was modelled using docking simulations. The series was expanded based on key target interactions involving residues known to impart N-domain selectivity. In total, seven diprolyl compounds were synthesised and tested for N-domain selective ACE inhibition. One compound with an aspartic acid in the P2 position (compound 16) displayed potent inhibition (Ki = 12 nM), and was 84-fold more selective towards the N-domain. A high-resolution crystal structure of compound 16 in complex with the N-domain revealed the molecular basis for the observed selectivity.

The Design and Development of a Potent and Selective Novel Diprolyl Derivative that Binds to the N-domain of Angiotensin-I Converting Enzyme.,Fienberg S, Cozier GE, Acharya KR, Chibale K, Sturrock ED J Med Chem. 2017 Dec 5. doi: 10.1021/acs.jmedchem.7b01478. PMID:29206036<ref>PMID:29206036</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6en6" style="background-color:#fffaf0;"></div>

==See Also==
*[[Angiotensin-Converting Enzyme 3D structures|Angiotensin-Converting Enzyme 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Acharya KR]]
[[Category: Chibale K]]
[[Category: Cozier GE]]
[[Category: Fienberg S]]
[[Category: Sturrock ED]]