6zpu
Crystal structure of Angiotensin-1 converting enzyme C-domain with inserted symmetry molecule C-terminus.Crystal structure of Angiotensin-1 converting enzyme C-domain with inserted symmetry molecule C-terminus.
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. Publication Abstract from PubMedAngiotensin-1 converting enzyme (ACE) is a key enzyme in the renin-angiotensin-aldosterone and kinin systems where it cleaves angiotensin I and bradykinin peptides, respectively. However, ACE also participates in numerous other physiological functions, can hydrolyse many peptide substrates, and has various exo- and endopeptidase activities. ACE achieves this complexity by containing two homologous catalytic domains (N- and C-domains), which exhibit different substrate specificities. Here we present the first open conformation structures of ACE N-domain, and a unique closed C-domain structure (2.0 A) where the C-terminus of a symmetry-related molecule is observed inserted into the active site cavity and binding to the zinc ion. The open native N-domain structure (1.85 A) enables comparison with ACE2, a homologue previously observed in open and closed states. An open S2 _S'-mutant N-domain structure (2.80 A) includes mutated residues in the S2 - and S'- subsites that effect ligand binding, but are distal to the binding site. Analysis of these structures provides important insights into how structural features of the ACE domains are able to accommodate the wide variety of substrates and allow different peptidase activities. Angiotensin-converting enzyme open for business: structural insights into the sub-domain dynamics.,Cozier GE, Lubbe L, Sturrock ED, Acharya KR FEBS J. 2020 Oct 17. doi: 10.1111/febs.15601. PMID:33067882[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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