| Structural highlights
7npk is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | GOL, UL2 |
| Gene: | SERPINA1, AAT, PI, PRO0684, PRO2209 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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 PubMed
alpha1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant alpha1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z alpha1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active alpha1-antitrypsin correctors.
The development of highly potent and selective small molecule correctors of Z alpha1-antitrypsin misfolding.,Liddle J, Pearce AC, Arico-Muendel C, Belyanskaya S, Brewster A, Brown M, Chung CW, Denis A, Dodic N, Dossang A, Eddershaw P, Klimaszewska D, Haq I, Holmes DS, Jagger A, Jakhria T, Jigorel E, Lind K, Messer J, Neu M, Olszewski A, Ronzoni R, Rowedder J, Rudiger M, Skinner S, Smith KJ, Trottet L, Uings I, Zhu Z, Irving JA, Lomas DA Bioorg Med Chem Lett. 2021 Mar 19;41:127973. doi: 10.1016/j.bmcl.2021.127973. PMID:33753261[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Seyama K, Nukiwa T, Takabe K, Takahashi H, Miyake K, Kira S. Siiyama (serine 53 (TCC) to phenylalanine 53 (TTC)). A new alpha 1-antitrypsin-deficient variant with mutation on a predicted conserved residue of the serpin backbone. J Biol Chem. 1991 Jul 5;266(19):12627-32. PMID:1905728
- ↑ Holmes MD, Brantly ML, Fells GA, Crystal RG. Alpha 1-antitrypsin Wbethesda: molecular basis of an unusual alpha 1-antitrypsin deficiency variant. Biochem Biophys Res Commun. 1990 Aug 16;170(3):1013-20. PMID:2390072
- ↑ Graham A, Kalsheker NA, Bamforth FJ, Newton CR, Markham AF. Molecular characterisation of two alpha-1-antitrypsin deficiency variants: proteinase inhibitor (Pi) Null(Newport) (Gly115----Ser) and (Pi) Z Wrexham (Ser-19----Leu). Hum Genet. 1990 Oct;85(5):537-40. PMID:2227940
- ↑ Tanaka N, Sekiya S, Takamizawa H, Kato N, Moriyama Y, Fujimura S. Characterization of a 54 kDa, alpha 1-antitrypsin-like protein isolated from ascitic fluid of an endometrial cancer patient. Jpn J Cancer Res. 1991 Jun;82(6):693-700. PMID:1906855
- ↑ Niemann MA, Narkates AJ, Miller EJ. Isolation and serine protease inhibitory activity of the 44-residue, C-terminal fragment of alpha 1-antitrypsin from human placenta. Matrix. 1992 Jun;12(3):233-41. PMID:1406456
- ↑ Tanaka N, Sekiya S, Takamizawa H, Kato N, Moriyama Y, Fujimura S. Characterization of a 54 kDa, alpha 1-antitrypsin-like protein isolated from ascitic fluid of an endometrial cancer patient. Jpn J Cancer Res. 1991 Jun;82(6):693-700. PMID:1906855
- ↑ Niemann MA, Narkates AJ, Miller EJ. Isolation and serine protease inhibitory activity of the 44-residue, C-terminal fragment of alpha 1-antitrypsin from human placenta. Matrix. 1992 Jun;12(3):233-41. PMID:1406456
- ↑ Liddle J, Pearce AC, Arico-Muendel C, Belyanskaya S, Brewster A, Brown M, Chung CW, Denis A, Dodic N, Dossang A, Eddershaw P, Klimaszewska D, Haq I, Holmes DS, Jagger A, Jakhria T, Jigorel E, Lind K, Messer J, Neu M, Olszewski A, Ronzoni R, Rowedder J, Rudiger M, Skinner S, Smith KJ, Trottet L, Uings I, Zhu Z, Irving JA, Lomas DA. The development of highly potent and selective small molecule correctors of Z alpha1-antitrypsin misfolding. Bioorg Med Chem Lett. 2021 Mar 19;41:127973. doi: 10.1016/j.bmcl.2021.127973. PMID:33753261 doi:https://dx.doi.org/10.1016/j.bmcl.2021.127973
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