6I3Z
Fab fragment of an antibody selective for wild-type alpha-1-antitrypsin in complex with its antigen
Summary for 6I3Z
| Entry DOI | 10.2210/pdb6i3z/pdb |
| Related | 6IO1 |
| Descriptor | Alpha-1-antitrypsin, Fab 2H2 heavy chain, Fab 2H2 light chain, ... (7 entities in total) |
| Functional Keywords | antibody fragment, antitrypsin binding, diagnostic, monoclonal, protein binding, selective, wild-type, glu342, e342 |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 91886.18 |
| Authors | Laffranchi, M.,Elliston, E.L.K.,Miranda, E.,Perez, J.,Jagger, A.M.,Fra, A.,Lomas, D.A.,Irving, J.A. (deposition date: 2018-11-08, release date: 2019-11-20, Last modification date: 2024-11-13) |
| Primary citation | Laffranchi, M.,Elliston, E.L.,Miranda, E.,Perez, J.,Ronzoni, R.,Jagger, A.M.,Heyer-Chauhan, N.,Brantly, M.L.,Fra, A.,Lomas, D.A.,Irving, J.A. Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin. JCI Insight, 5:-, 2020 Cited by PubMed Abstract: The α-1-antitrypsin (or alpha-1-antitrypsin, A1AT) Z variant is the primary cause of severe A1AT deficiency and forms polymeric chains that aggregate in the endoplasmic reticulum of hepatocytes. Around 2%-5% of Europeans are heterozygous for the Z and WT M allele, and there is evidence of increased risk of liver disease when compared with MM A1AT individuals. We have shown that Z and M A1AT can copolymerize in cell models, but there has been no direct observation of heteropolymer formation in vivo. To this end, we developed a monoclonal antibody (mAb2H2) that specifically binds to M in preference to Z A1AT, localized its epitope using crystallography to a region perturbed by the Z (Glu342Lys) substitution, and used Fab fragments to label polymers isolated from an MZ heterozygote liver explant. Glu342 is critical to the affinity of mAb2H2, since it also recognized the mild S-deficiency variant (Glu264Val) present in circulating polymers from SZ heterozygotes. Negative-stain electron microscopy of the Fab2H2-labeled liver polymers revealed that M comprises around 6% of the polymer subunits in the MZ liver sample. These data demonstrate that Z A1AT can form heteropolymers with polymerization-inert variants in vivo with implications for liver disease in heterozygous individuals. PubMed: 32699193DOI: 10.1172/jci.insight.135459 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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