View source for 9qas


==Human angiotensin-1 converting enzyme N-domain in complex with trandolaprilat==
<StructureSection load='9qas' size='340' side='right'caption='[[9qas]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9qas]] 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=9QAS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9QAS 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]] 2.2&#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=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=X93:TRANDOLAPRILAT'>X93</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=9qas FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9qas OCA], [https://pdbe.org/9qas PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9qas RCSB], [https://www.ebi.ac.uk/pdbsum/9qas PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9qas 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 dipeptidyl carboxypeptidase with two homologous catalytic domains [N- and C-domains (nACE and cACE)] that can cleave a range of substrates. cACE primarily cleaves the inactive decapeptide angiotensin I into the potent vasopressor angiotensin II, whereas nACE preferentially cleaves the antifibrotic tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Several ACE inhibitors, which bind to both cACE and nACE active sites, are used clinically for the treatment of hypertension; however, serious side effects are seen in ~ 20-25% of patients due to nonselective inhibition. To improve ACE inhibitor side effect profiles, the design and development of selective inhibitors of cACE or nACE is desirable for the treatment of hypertension or fibrosis. The detailed molecular basis through which the clinically available ACE inhibitors bind and inhibit cACE and nACE was unknown. Thus, in this study, we have characterised the structural and kinetic basis for the interaction between cACE and nACE with enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat. The inhibitors display nanomolar inhibition of both domains, with moderate-to-low cACE-selectivity. Trandolaprilat possesses the highest affinity for both nACE and cACE, whereas quinaprilat displayed the largest cACE-selectivity. None of the binding modes of the inhibitors extend beyond the S1-S2' subsites to make use of the unique nACE/cACE residues that have been shown to influence domain selectivity. These findings supplement our understanding of ACE inhibition by the clinically used ACE inhibitors, and this information should be useful in the future design of more domain-selective inhibitors for the treatment of hypertension and cardiovascular diseases.

Molecular basis of domain-specific angiotensin I-converting enzyme inhibition by the antihypertensive drugs enalaprilat, ramiprilat, trandolaprilat, quinaprilat and perindoprilat.,Gregory KS, Ramasamy V, Sturrock ED, Acharya KR FEBS J. 2025 Aug 18. doi: 10.1111/febs.70232. PMID:40824896<ref>PMID:40824896</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9qas" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Acharya KR]]
[[Category: Gregory KS]]