Summary for 7AEL
| Entry DOI | 10.2210/pdb7ael/pdb |
| Descriptor | Alpha-1-antitrypsin, ~{N}-[(1~{S},2~{R})-1-(3-fluoranyl-2-methyl-phenyl)-1-oxidanyl-pentan-2-yl]-2-oxidanylidene-1,3-dihydroindole-4-carboxamide, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | serpin, serine protease inhibitor, protein binding |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 46062.16 |
| Authors | Chung, C. (deposition date: 2020-09-17, release date: 2021-03-10, Last modification date: 2024-05-01) |
| Primary citation | Lomas, D.A.,Irving, J.A.,Arico-Muendel, C.,Belyanskaya, S.,Brewster, A.,Brown, M.,Chung, C.W.,Dave, H.,Denis, A.,Dodic, N.,Dossang, A.,Eddershaw, P.,Klimaszewska, D.,Haq, I.,Holmes, D.S.,Hutchinson, J.P.,Jagger, A.M.,Jakhria, T.,Jigorel, E.,Liddle, J.,Lind, K.,Marciniak, S.J.,Messer, J.,Neu, M.,Olszewski, A.,Ordonez, A.,Ronzoni, R.,Rowedder, J.,Rudiger, M.,Skinner, S.,Smith, K.J.,Terry, R.,Trottet, L.,Uings, I.,Wilson, S.,Zhu, Z.,Pearce, A.C. Development of a small molecule that corrects misfolding and increases secretion of Z alpha 1 -antitrypsin. Embo Mol Med, 13:e13167-e13167, 2021 Cited by PubMed Abstract: Severe α -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α -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 α -antitrypsin. The lead compound blocks Z α -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α -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 α -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 α -antitrypsin deficiency. PubMed: 33512066DOI: 10.15252/emmm.202013167 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.76 Å) |
Structure validation
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