9gbp
Human Angiotensin-1 converting enzyme N-domain in complex with a diprolyl inhibitor- SG3
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 zinc-dependent carboxypeptidase of therapeutic interest for the treatment of hypertension, inflammation and fibrosis. It consists of two homologous N and C catalytic domains, nACE and cACE, respectively. Unfortunately, the current clinically available ACE inhibitors produce undesirable side effects due to the nonselective inhibition of these domains. Through structure-based drug design, we previously identified a series of diprolyl-derived inhibitors (SG3, SG15, SG16, SG17 and SG18) in an attempt to specifically target nACE. Only one compound, SG16, possessed significant nACEselectivity. The previously determined 16-nACE crystal structure (nACE:SG16) suggested interactions with Tyr369 (Phe381 in cACE) are responsible for this selectivity. To better understand the molecular basis for the lack of selectivity in the remaining compounds, we have cocrystallised nACE in complex with SG3, SG15, SG17 and SG18 and cACE in complex with SG3, SG15, SG16 and SG18 and determined their structures at high resolution. Apart from the catalytic residues, these structures further highlight the importance of residues distal to the active site that may play an important role in the design of domain-selective inhibitors of ACE. Molecular basis of human angiotensin-1 converting enzyme inhibition by a series of diprolyl-derived compounds.,Gregory KS, Cozier GE, Fienberg S, Chibale K, Sturrock ED, Acharya KR FEBS J. 2025 Jan 6. doi: 10.1111/febs.17384. PMID:39763019[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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