1qmb

From Proteopedia

(Difference between revisions)

Revision as of 07:02, 6 January 2015

CLEAVED ALPHA-1-ANTITRYPSIN POLYMER

Structural highlights

1qmb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	7api, 8api, 9api, 1psi, 2psi, 1kct, 1atu
Resources:	FirstGlance, OCA, RCSB, PDBsum

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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The function of the serpins as proteinase inhibitors depends on their ability to insert the cleaved reactive centre loop as the fourth strand in the main A beta-sheet of the molecule upon proteolytic attack at the reactive centre, P1-P1'. This mechanism is vulnerable to mutations which result in inappropriate intra- or intermolecular loop insertion in the absence of cleavage. Intermolecular loop insertion is known as serpin polymerisation and results in a variety of diseases, most notably liver cirrhosis resulting from mutations of the prototypical serpin alpha1-antitrypsin. We present here the 2.6 A structure of a polymer of alpha1-antitrypsin cleaved six residues N-terminal to the reactive centre, P7-P6 (Phe352-Leu353). After self insertion of P14 to P7, intermolecular linkage is affected by insertion of the P6-P3 residues of one molecule into the partially occupied beta-sheet A of another. This results in an infinite, linear polymer which propagates in the crystal along a 2-fold screw axis. These findings provide a framework for understanding the uncleaved alpha1-antitrypsin polymer and fibrillar and amyloid deposition of proteins seen in other conformational diseases, with the ordered array of polymers in the crystal resulting from slow accretion of the cleaved serpin over the period of a year.

A 2.6 A structure of a serpin polymer and implications for conformational disease.,Huntington JA, Pannu NS, Hazes B, Read RJ, Lomas DA, Carrell RW J Mol Biol. 1999 Oct 29;293(3):449-55. PMID:10543942^[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
↑ Huntington JA, Pannu NS, Hazes B, Read RJ, Lomas DA, Carrell RW. A 2.6 A structure of a serpin polymer and implications for conformational disease. J Mol Biol. 1999 Oct 29;293(3):449-55. PMID:10543942 doi:10.1006/jmbi.1999.3184

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1qmb"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1qmb]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QMB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1QMB FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[7api|7api]], [[8api|8api]], [[9api|9api]], [[1psi|1psi]], [[2psi|2psi]], [[1kct|1kct]], [[1atu|1atu]]</td></tr>
+</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[7api|7api]], [[8api|8api]], [[9api|9api]], [[1psi|1psi]], [[2psi|2psi]], [[1kct|1kct]], [[1atu|1atu]]</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1qmb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1qmb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1qmb RCSB], [http://www.ebi.ac.uk/pdbsum/1qmb PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1qmb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1qmb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1qmb RCSB], [http://www.ebi.ac.uk/pdbsum/1qmb PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://www.uniprot.org/uniprot/A1AT_HUMAN A1AT_HUMAN]] Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:[http://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>
@@ Line 36: / Line 36: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Carrell, R W.]]
+[[Category: Carrell, R W]]
-[[Category: Hazes, B.]]
+[[Category: Hazes, B]]
-[[Category: Huntington, J A.]]
+[[Category: Huntington, J A]]
-[[Category: Lomas, D A.]]
+[[Category: Lomas, D A]]
-[[Category: Pannu, N S.]]
+[[Category: Pannu, N S]]
-[[Category: Read, R J.]]
+[[Category: Read, R J]]
 [[Category: Antitrypsin]]
 [[Category: Cleaved]]

1qmb

From Proteopedia

Revision as of 07:02, 6 January 2015

CLEAVED ALPHA-1-ANTITRYPSIN POLYMER

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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