7ael
From Proteopedia
alpha 1-antitrypsin (C232S) complexed with GSK716
Structural highlights
Disease[A1AT_HUMAN] Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:613490]. A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age.[1] [2] [3] Function[A1AT_HUMAN] Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.[:][4] [5] Short peptide from AAT: reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).[:][6] [7] Publication Abstract from PubMedSevere alpha1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant alpha1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z alpha1 -antitrypsin. The lead compound blocks Z alpha1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z alpha1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z alpha1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z alpha1 -antitrypsin deficiency. Development of a small molecule that corrects misfolding and increases secretion of Z alpha1 -antitrypsin.,Lomas DA, Irving JA, Arico-Muendel C, Belyanskaya S, Brewster A, Brown M, Chung CW, Dave H, Denis A, Dodic N, Dossang A, Eddershaw P, Klimaszewska D, Haq I, Holmes DS, Hutchinson JP, Jagger AM, Jakhria T, Jigorel E, Liddle J, Lind K, Marciniak SJ, Messer J, Neu M, Olszewski A, Ordonez A, Ronzoni R, Rowedder J, Rudiger M, Skinner S, Smith KJ, Terry R, Trottet L, Uings I, Wilson S, Zhu Z, Pearce AC EMBO Mol Med. 2021 Mar 5;13(3):e13167. doi: 10.15252/emmm.202013167. Epub 2021, Jan 29. PMID:33512066[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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