9hud

From Proteopedia

(Difference between revisions)

Current revision

Alpha-1-antitrypsin in the cleaved conformation in complex with a conformationally nonselective Fab fragment

Structural highlights

9hud is a 8 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.42Å
Ligands:	, , , , ,
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

Originating 2 to 3 millennia ago in a Scandinavian population, the SERPINA1 Z allele (Glu342Lys) is present in up to 2.5% of populations of Northern European descent and accounts for 95% of severe alpha(1)-antitrypsin deficiency. The alpha(1)-antitrypsin Z variant self-assembles into polymer chains that deposit within hepatocytes, predisposing to liver disease. Here, the 4.0A subunit structure of polymers isolated directly from human liver tissue has been determined using cryoelectron microscopy. Challenges of flexibility, small subunit size, heterogeneous length, and preferred orientations were mitigated using antibody Fab domains and sample preparation strategies. This structure demonstrates that the formation of polymers in vivo involves self-incorporation of an exposed structural element (the reactive center loop) as an additional beta-strand into the central beta-sheet of alpha(1)-antitrypsin and displacement of a C-terminal region from one subunit with incorporation into the next. Unlike amyloid aggregation, this well-folded structure partially recapitulates a conformation adopted during normal function of the protein. These perturbations to the constituent alpha(1)-antitrypsin subunits of human tissue-derived polymers are consistent with a pronounced stability, their tendency toward long-chain forms, the ability of a subset to undergo canonical secretion, and the action of a class of small molecules that block polymerization in vivo.

The mechanism of pathogenic alpha(1)-antitrypsin aggregation in the human liver.,Aldobiyan I, Elliston ELK, Heyer-Chauhan N, Arold ST, Zhao L, Huntington B, Lowen SM, Orlova EV, Irving JA, Lomas DA Proc Natl Acad Sci U S A. 2025 Nov 18;122(46):e2507535122. doi: , 10.1073/pnas.2507535122. Epub 2025 Nov 13. PMID:41231946^[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
↑ Aldobiyan I, Elliston ELK, Heyer-Chauhan N, Arold ST, Zhao L, Huntington B, Lowen SM, Orlova EV, Irving JA, Lomas DA. The mechanism of pathogenic α(1)-antitrypsin aggregation in the human liver. Proc Natl Acad Sci U S A. 2025 Nov 18;122(46):e2507535122. PMID:41231946 doi:10.1073/pnas.2507535122

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9hud"

Categories: Homo sapiens | Large Structures | Mus musculus | Aldobiyan IF | Irving JA

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9hud is ON HOLD  until Paper Publication
+==Alpha-1-antitrypsin in the cleaved conformation in complex with a conformationally nonselective Fab fragment==
+<StructureSection load='9hud' size='340' side='right'caption='[[9hud]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9hud]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9HUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HUD FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.42&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9hud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hud OCA], [https://pdbe.org/9hud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hud RCSB], [https://www.ebi.ac.uk/pdbsum/9hud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hud ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/A1AT_HUMAN A1AT_HUMAN] Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:[https://omim.org/entry/613490 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.<ref>PMID:1905728</ref> <ref>PMID:2390072</ref> <ref>PMID:2227940</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/A1AT_HUMAN 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.[:]<ref>PMID:1906855</ref> <ref>PMID:1406456</ref>   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).[:]<ref>PMID:1906855</ref> <ref>PMID:1406456</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Originating 2 to 3 millennia ago in a Scandinavian population, the SERPINA1 Z allele (Glu342Lys) is present in up to 2.5% of populations of Northern European descent and accounts for 95% of severe alpha(1)-antitrypsin deficiency. The alpha(1)-antitrypsin Z variant self-assembles into polymer chains that deposit within hepatocytes, predisposing to liver disease. Here, the 4.0A subunit structure of polymers isolated directly from human liver tissue has been determined using cryoelectron microscopy. Challenges of flexibility, small subunit size, heterogeneous length, and preferred orientations were mitigated using antibody Fab domains and sample preparation strategies. This structure demonstrates that the formation of polymers in vivo involves self-incorporation of an exposed structural element (the reactive center loop) as an additional beta-strand into the central beta-sheet of alpha(1)-antitrypsin and displacement of a C-terminal region from one subunit with incorporation into the next. Unlike amyloid aggregation, this well-folded structure partially recapitulates a conformation adopted during normal function of the protein. These perturbations to the constituent alpha(1)-antitrypsin subunits of human tissue-derived polymers are consistent with a pronounced stability, their tendency toward long-chain forms, the ability of a subset to undergo canonical secretion, and the action of a class of small molecules that block polymerization in vivo.
-Authors: Irving, J.A., Aldobiyan, I.F.
+The mechanism of pathogenic alpha(1)-antitrypsin aggregation in the human liver.,Aldobiyan I, Elliston ELK, Heyer-Chauhan N, Arold ST, Zhao L, Huntington B, Lowen SM, Orlova EV, Irving JA, Lomas DA Proc Natl Acad Sci U S A. 2025 Nov 18;122(46):e2507535122. doi: , 10.1073/pnas.2507535122. Epub 2025 Nov 13. PMID:41231946<ref>PMID:41231946</ref>
-Description: Alpha-1-antitrypsin in the cleaved conformation in complex with a conformationally unselective Fab fragment
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Aldobiyan, I.F]]
+<div class="pdbe-citations 9hud" style="background-color:#fffaf0;"></div>
-[[Category: Irving, J.A]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Aldobiyan IF]]
+[[Category: Irving JA]]

9hud

From Proteopedia

Current revision

Alpha-1-antitrypsin in the cleaved conformation in complex with a conformationally nonselective Fab fragment

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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