PDBsum entry 1psi

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protein links
Serine protease inhibitor PDB id
Protein chain
372 a.a. *
* Residue conservation analysis
PDB id:
Name: Serine protease inhibitor
Title: Intact recombined alpha1-antitrypsin mutant phe 51 to leu
Structure: Alpha=1=-antitrypsin. Chain: a. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Tissue: blood plasma. Gene: alpha-1-antitrypsin. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.92Å     R-factor:   0.218     R-free:   0.288
Authors: J.P.Abrahams,P.R.Elliott,D.A.Lomas,R.W.Carrell
Key ref: P.R.Elliott et al. (1996). Inhibitory conformation of the reactive loop of alpha 1-antitrypsin. Nat Struct Biol, 3, 676-681. PubMed id: 8756325
11-Jun-96     Release date:   07-Dec-96    
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Protein chain
Pfam   ArchSchema ?
P01009  (A1AT_HUMAN) -  Alpha-1-antitrypsin
418 a.a.
372 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   6 terms 
  Biological process     response to inorganic substance   19 terms 
  Biochemical function     protein binding     6 terms  


Nat Struct Biol 3:676-681 (1996)
PubMed id: 8756325  
Inhibitory conformation of the reactive loop of alpha 1-antitrypsin.
P.R.Elliott, D.A.Lomas, R.W.Carrell, J.P.Abrahams.
The reactive site loop of the serpin family of serine proteinase inhibitors is flexible and can adopt a number of diverse conformations. A 2.9 A resolution structure of alpha 1-antitrypsin-the principal proteinase inhibitor in human plasma-shows the loop in a stable canonical conformation matching that found in all other families of serine proteinase inhibitors. This unexpected finding in the absence of loop insertion into the body of the molecule favours a two-stage mechanism of inhibition and provides a model for the heparin activation of antithrombin. The beta-pleated strand conformation of the loop also accounts for the polymerization of the serpins in disease and for their association with other beta-sheet structures, most notably the beta-amyloid of Alzheimer's disease.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20583215 E.Miranda, J.Pérez, U.I.Ekeowa, N.Hadzic, N.Kalsheker, B.Gooptu, B.Portmann, D.Belorgey, M.Hill, S.Chambers, J.Teckman, G.J.Alexander, S.J.Marciniak, and D.A.Lomas (2010).
A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency.
  Hepatology, 52, 1078-1088.  
20199147 S.Bae, J.Choi, J.Hong, S.Lee, E.Her, W.Choi, S.Kim, Y.Choi, and S.Kim (2010).
Generation of anti-proteinase 3 monoclonal antibodies and development of immunological methods to detect endogenous proteinase 3.
  Hybridoma (Larchmt), 29, 17-26.  
19245336 B.Gooptu, and D.A.Lomas (2009).
Conformational pathology of the serpins: themes, variations, and therapeutic strategies.
  Annu Rev Biochem, 78, 147-176.  
19689240 C.L.Maarouf, T.M.Andacht, T.A.Kokjohn, E.M.Castaño, L.I.Sue, T.G.Beach, and A.E.Roher (2009).
Proteomic analysis of Alzheimer's disease cerebrospinal fluid from neuropathologically diagnosed subjects.
  Curr Alzheimer Res, 6, 399-406.  
19258393 D.J.Termine, K.W.Moremen, and R.N.Sifers (2009).
The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I.
  J Cell Sci, 122, 976-984.  
  18688041 R.H.Hubner, P.L.Leopold, M.Kiuru, B.P.De, A.Krause, and R.G.Crystal (2009).
Dysfunctional glycogen storage in a mouse model of alpha1-antitrypsin deficiency.
  Am J Respir Cell Mol Biol, 40, 239-247.  
19426146 U.I.Ekeowa, B.Gooptu, D.Belorgey, P.Hägglöf, S.Karlsson-Li, E.Miranda, J.Pérez, I.MacLeod, H.Kroger, S.J.Marciniak, D.C.Crowther, and D.A.Lomas (2009).
alpha1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies.
  Clin Sci (Lond), 116, 837-850.  
19120695 Y.P.Chang, R.Mahadeva, W.S.Chang, S.C.Lin, and Y.H.Chu (2009).
Small-molecule peptides inhibit Z alpha1-antitrypsin polymerization.
  J Cell Mol Med, 13, 2304-2316.  
18267959 E.Miranda, I.MacLeod, M.J.Davies, J.Pérez, K.Römisch, D.C.Crowther, and D.A.Lomas (2008).
The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB.
  Hum Mol Genet, 17, 1527-1539.  
18352854 G.A.Heresi, and J.K.Stoller (2008).
Augmentation therapy in alpha-1 antitrypsin deficiency.
  Expert Opin Biol Ther, 8, 515-526.  
18729734 S.M.Best (2008).
Viral subversion of apoptotic enzymes: escape from death row.
  Annu Rev Microbiol, 62, 171-192.  
  19164889 D.Belorgey, P.Hägglöf, S.Karlsson-Li, and D.A.Lomas (2007).
Protein misfolding and the serpinopathies.
  Prion, 1, 15-20.  
17442346 P.Chowdhury, W.Wang, S.Lavender, M.R.Bunagan, J.W.Klemke, J.Tang, J.G.Saven, B.S.Cooperman, and F.Gai (2007).
Fluorescence correlation spectroscopic study of serpin depolymerization by computationally designed peptides.
  J Mol Biol, 369, 462-473.  
16835244 A.S.Robertson, D.Belorgey, D.Gubb, T.R.Dafforn, and D.A.Lomas (2006).
Inhibitory activity of the Drosophila melanogaster serpin Necrotic is dependent on lysine residues in the D-helix.
  J Biol Chem, 281, 26437-26443.  
16773239 E.Karnaukhova, Y.Ophir, and B.Golding (2006).
Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use.
  Amino Acids, 30, 317-332.  
16820297 J.A.Huntington (2006).
Shape-shifting serpins--advantages of a mobile mechanism.
  Trends Biochem Sci, 31, 427-435.  
17079131 J.C.Whisstock, and S.P.Bottomley (2006).
Molecular gymnastics: serpin structure, folding and misfolding.
  Curr Opin Struct Biol, 16, 761-768.  
16849336 K.J.Kinghorn, D.C.Crowther, L.K.Sharp, C.Nerelius, R.L.Davis, H.T.Chang, C.Green, D.C.Gubb, J.Johansson, and D.A.Lomas (2006).
Neuroserpin binds Abeta and is a neuroprotective component of amyloid plaques in Alzheimer disease.
  J Biol Chem, 281, 29268-29277.  
16704419 L.K.Sharp, M.Mallya, K.J.Kinghorn, Z.Wang, D.C.Crowther, J.A.Huntington, D.Belorgey, and D.A.Lomas (2006).
Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis.
  FEBS J, 273, 2540-2552.  
16737556 R.H.Law, Q.Zhang, S.McGowan, A.M.Buckle, G.A.Silverman, W.Wong, C.J.Rosado, C.G.Langendorf, R.N.Pike, P.I.Bird, and J.C.Whisstock (2006).
An overview of the serpin superfamily.
  Genome Biol, 7, 216.  
15659365 E.K.Dufour, A.Désilets, J.M.Longpré, and R.Leduc (2005).
Stability of mutant serpin/furin complexes: dependence on pH and regulation at the deacylation step.
  Protein Sci, 14, 303-315.  
15664988 M.Onda, D.Belorgey, L.K.Sharp, and D.A.Lomas (2005).
Latent S49P neuroserpin forms polymers in the dementia familial encephalopathy with neuroserpin inclusion bodies.
  J Biol Chem, 280, 13735-13741.  
15576554 Y.R.Na, and H.Im (2005).
The length of the reactive center loop modulates the latency transition of plasminogen activator inhibitor-1.
  Protein Sci, 14, 55-63.  
14767073 C.H.Jung, Y.R.Na, and H.Im (2004).
Retarded protein folding of deficient human alpha 1-antitrypsin D256V and L41P variants.
  Protein Sci, 13, 694-702.  
15170041 D.A.Lomas, and H.Parfrey (2004).
Alpha1-antitrypsin deficiency. 4: Molecular pathophysiology.
  Thorax, 59, 529-535.  
15090543 E.Miranda, K.Römisch, and D.A.Lomas (2004).
Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum.
  J Biol Chem, 279, 28283-28291.  
15501821 M.Al-Ayyoubi, P.G.Gettins, and K.Volz (2004).
Crystal structure of human maspin, a serpin with antitumor properties: reactive center loop of maspin is exposed but constrained.
  J Biol Chem, 279, 55540-55544.
PDB codes: 1xqg 1xqj
12860985 A.Dementiev, M.Simonovic, K.Volz, and P.G.Gettins (2003).
Canonical inhibitor-like interactions explain reactivity of alpha1-proteinase inhibitor Pittsburgh and antithrombin with proteinases.
  J Biol Chem, 278, 37881-37887.
PDB codes: 1oo8 1oph
12414799 A.S.Robertson, D.Belorgey, K.S.Lilley, D.A.Lomas, D.Gubb, and T.R.Dafforn (2003).
Characterization of the necrotic protein that regulates the Toll-mediated immune response in Drosophila.
  J Biol Chem, 278, 6175-6180.  
12930828 E.M.Springhetti, N.E.Istomina, J.C.Whisstock, T.Nikitina, C.L.Woodcock, and S.A.Grigoryev (2003).
Role of the M-loop and reactive center loop domains in the folding and bridging of nucleosome arrays by MENT.
  J Biol Chem, 278, 43384-43393.  
12649292 E.Marszal, D.Danino, and A.Shrake (2003).
A novel mode of polymerization of alpha1-proteinase inhibitor.
  J Biol Chem, 278, 19611-19618.  
  12651876 P.Ferenci (2003).
How to identify the genetic basis of gastrointestinal and liver diseases?
  Gut, 52, ii6-ii9.  
  12464660 D.A.Lomas, and R.Mahadeva (2002).
Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy.
  J Clin Invest, 110, 1585-1590.  
12360234 D.A.Lomas, and R.W.Carrell (2002).
Serpinopathies and the conformational dementias.
  Nat Rev Genet, 3, 759-768.  
11971909 M.A.Jairajpuri, A.Lu, and S.C.Bock (2002).
Elimination of P1 arginine 393 interaction with underlying glutamic acid 255 partially activates antithrombin III for thrombin inhibition but not factor Xa inhibition.
  J Biol Chem, 277, 24460-24465.  
11854268 N.S.Quinsey, J.C.Whisstock, B.Le Bonniec, V.Louvain, S.P.Bottomley, and R.N.Pike (2002).
Molecular determinants of the mechanism underlying acceleration of the interaction between antithrombin and factor Xa by heparin pentasaccharide.
  J Biol Chem, 277, 15971-15978.  
12009885 S.W.Griffiths, and C.L.Cooney (2002).
Relationship between protein structure and methionine oxidation in recombinant human alpha 1-antitrypsin.
  Biochemistry, 41, 6245-6252.  
11555638 D.N.Saunders, L.Jankova, S.J.Harrop, P.M.Curmi, A.R.Gould, M.Ranson, and M.S.Baker (2001).
Interaction between the P14 residue and strand 2 of beta-sheet B is critical for reactive center loop insertion in plasminogen activator inhibitor-2.
  J Biol Chem, 276, 43383-43389.  
11159419 J.P.Ludeman, J.C.Whisstock, P.C.Hopkins, B.F.Le Bonniec, and S.P.Bottomley (2001).
Structure of a serpin-enzyme complex probed by cysteine substitutions and fluorescence spectroscopy.
  Biophys J, 80, 491-497.  
11714919 S.P.Bottomley, I.D.Lawrenson, D.Tew, W.Dai, J.C.Whisstock, and R.N.Pike (2001).
The role of strand 1 of the C beta-sheet in the structure and function of alpha(1)-antitrypsin.
  Protein Sci, 10, 2518-2524.  
10618372 B.Gooptu, B.Hazes, W.S.Chang, T.R.Dafforn, R.W.Carrell, R.J.Read, and D.A.Lomas (2000).
Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease.
  Proc Natl Acad Sci U S A, 97, 67-72.
PDB code: 1qmn
10954247 D.A.Lomas (2000).
Loop-sheet polymerization: the mechanism of alpha1-antitrypsin deficiency.
  Respir Med, 94, S3-S6.  
10744761 J.Célérier, G.Schmid, J.P.Le Caer, A.P.Gimenez-Roqueplo, D.Bur, A.Friedlein, H.Langen, P.Corvol, and X.Jeunemaitre (2000).
Characterization of a human angiotensinogen cleaved in its reactive center loop by a proteolytic activity from Chinese hamster ovary cells.
  J Biol Chem, 275, 10648-10654.  
10715104 L.Shen, B.Dahlbäck, and B.O.Villoutreix (2000).
Tracking structural features leading to resistance of activated protein C to alpha 1-antitrypsin.
  Biochemistry, 39, 2853-2860.  
  10716194 M.A.Dunstone, W.Dai, J.C.Whisstock, J.Rossjohn, R.N.Pike, S.C.Feil, B.F.Le Bonniec, M.W.Parker, and S.P.Bottomley (2000).
Cleaved antitrypsin polymers at atomic resolution.
  Protein Sci, 9, 417-420.
PDB code: 1d5s
  10933492 P.R.Elliott, X.Y.Pei, T.R.Dafforn, and D.A.Lomas (2000).
Topography of a 2.0 A structure of alpha1-antitrypsin reveals targets for rational drug design to prevent conformational disease.
  Protein Sci, 9, 1274-1281.
PDB code: 1qlp
10920033 R.Bauer, R.Carrotta, C.Rischel, and L.Ogendal (2000).
Characterization and isolation of intermediates in beta-lactoglobulin heat aggregation at high pH.
  Biophys J, 79, 1030-1038.  
10380350 A.Lombardi, G.De Simone, S.Galdiero, N.Staiano, F.Nastri, and V.Pavone (1999).
From natural to synthetic multisite thrombin inhibitors.
  Biopolymers, 51, 19-39.  
10092631 E.L.James, J.C.Whisstock, M.G.Gore, and S.P.Bottomley (1999).
Probing the unfolding pathway of alpha1-antitrypsin.
  J Biol Chem, 274, 9482-9488.  
10536068 G.Döring (1999).
Serine proteinase inhibitor therapy in alpha(1)-antitrypsin inhibitor deficiency and cystic fibrosis.
  Pediatr Pulmonol, 28, 363-375.  
10329708 H.Grasberger, C.Buettner, and O.E.Janssen (1999).
Modularity of serpins. A bifunctional chimera possessing alpha1-proteinase inhibitor and thyroxine-binding globulin properties.
  J Biol Chem, 274, 15046-15051.  
10196190 H.Im, E.J.Seo, and M.H.Yu (1999).
Metastability in the inhibitory mechanism of human alpha1-antitrypsin.
  J Biol Chem, 274, 11072-11077.  
  10595921 R.L.Davis, P.D.Holohan, A.E.Shrimpton, A.H.Tatum, J.Daucher, G.H.Collins, R.Todd, C.Bradshaw, P.Kent, D.Feiglin, A.Rosenbaum, M.S.Yerby, C.M.Shaw, F.Lacbawan, and D.A.Lawrence (1999).
Familial encephalopathy with neuroserpin inclusion bodies.
  Am J Pathol, 155, 1901-1913.  
10194472 R.Mahadeva, W.S.Chang, T.R.Dafforn, D.J.Oakley, R.C.Foreman, J.Calvin, D.G.Wight, and D.A.Lomas (1999).
Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis.
  J Clin Invest, 103, 999.  
10406969 T.Kirkegaard, S.Jensen, S.L.Schousboe, H.H.Petersen, R.Egelund, P.A.Andreasen, and K.W.Rodenburg (1999).
Engineering of conformations of plasminogen activator inhibitor-1. A crucial role of beta-strand 5A residues in the transition of active form to latent and substrate forms.
  Eur J Biochem, 263, 577-586.  
10092640 T.R.Dafforn, R.Mahadeva, P.R.Elliott, P.Sivasothy, and D.A.Lomas (1999).
A kinetic mechanism for the polymerization of alpha1-antitrypsin.
  J Biol Chem, 274, 9548-9555.  
9988693 V.Picard, P.E.Marque, F.Paolucci, M.Aiach, and B.F.Le Bonniec (1999).
Topology of the stable serpin-protease complexes revealed by an autoantibody that fails to react with the monomeric conformers of antithrombin.
  J Biol Chem, 274, 4586-4593.  
9748317 A.Futamura, E.Stratikos, S.T.Olson, and P.G.Gettins (1998).
Change in environment of the P1 side chain upon progression from the Michaelis complex to the covalent serpin-proteinase complex.
  Biochemistry, 37, 13110-13119.  
9468513 C.E.Chaillan-Huntington, and P.A.Patston (1998).
Influence of the P5 residue on alpha1-proteinase inhibitor mechanism.
  J Biol Chem, 273, 4569-4573.  
9521649 C.M.Lukacs, H.Rubin, and D.W.Christianson (1998).
Engineering an anion-binding cavity in antichymotrypsin modulates the "spring-loaded" serpin-protease interaction.
  Biochemistry, 37, 3297-3304.
PDB codes: 1as4 3caa 4caa
9636142 F.Jean, K.Stella, L.Thomas, G.Liu, Y.Xiang, A.J.Reason, and G.Thomas (1998).
alpha1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent.
  Proc Natl Acad Sci U S A, 95, 7293-7298.  
9521646 J.A.Huntington, and P.G.Gettins (1998).
Conformational conversion of antithrombin to a fully activated substrate of factor Xa without need for heparin.
  Biochemistry, 37, 3272-3277.  
9538691 J.Whisstock, R.Skinner, and A.M.Lesk (1998).
An atlas of serpin conformations.
  Trends Biochem Sci, 23, 63-67.  
  9713452 R.Mahadeva, and D.A.Lomas (1998).
Genetics and respiratory disease. 2. Alpha 1-antitrypsin deficiency, cirrhosis and emphysema.
  Thorax, 53, 501-505.  
9914261 R.W.Carrell, and B.Gooptu (1998).
Conformational changes and disease--serpins, prions and Alzheimer's.
  Curr Opin Struct Biol, 8, 799-809.  
9236002 C.E.Chaillan-Huntington, P.G.Gettins, J.A.Huntington, and P.A.Patston (1997).
The P6-P2 region of serpins is critical for proteinase inhibition and complex stability.
  Biochemistry, 36, 9562-9570.  
9154928 G.Kaslik, J.Kardos, E.Szabó, L.Szilágyi, P.Závodszky, W.M.Westler, J.L.Markley, and L.Gráf (1997).
Effects of serpin binding on the target proteinase: global stabilization, localized increased structural flexibility, and conserved hydrogen bonding at the active site.
  Biochemistry, 36, 5455-5464.  
  9348117 H.L.Fitton, R.N.Pike, R.W.Carrell, and W.S.Chang (1997).
Mechanisms of antithrombin polymerisation and heparin activation probed by the insertion of synthetic reactive loop peptides.
  Biol Chem, 378, 1059-1063.  
9154925 J.A.Huntington, B.Fan, K.E.Karlsson, J.Deinum, D.A.Lawrence, and P.G.Gettins (1997).
Serpin conformational change in ovalbumin. Enhanced reactive center loop insertion through hinge region mutations.
  Biochemistry, 36, 5432-5440.  
9405673 L.Jin, J.P.Abrahams, R.Skinner, M.Petitou, R.N.Pike, and R.W.Carrell (1997).
The anticoagulant activation of antithrombin by heparin.
  Proc Natl Acad Sci U S A, 94, 14683-14688.
PDB code: 1azx
9342229 R.Egelund, S.L.Schousboe, L.Sottrup-Jensen, K.W.Rodenburg, and P.A.Andreasen (1997).
Type-1 plasminogen-activator inhibitor -- conformational differences between latent, active, reactive-centre-cleaved and plasminogen-activator-complexed forms, as probed by proteolytic susceptibility.
  Eur J Biochem, 248, 775-785.  
9242619 R.N.Pike, J.Potempa, R.Skinner, H.L.Fitton, W.T.McGraw, J.Travis, M.Owen, L.Jin, and R.W.Carrell (1997).
Heparin-dependent modification of the reactive center arginine of antithrombin and consequent increase in heparin binding affinity.
  J Biol Chem, 272, 19652-19655.  
9228977 R.W.Carrell, and D.A.Lomas (1997).
Conformational disease.
  Lancet, 350, 134-138.  
  9007980 W.S.Chang, J.Whisstock, P.C.Hopkins, A.M.Lesk, R.W.Carrell, and M.R.Wardell (1997).
Importance of the release of strand 1C to the polymerization mechanism of inhibitory serpins.
  Protein Sci, 6, 89-98.  
8901864 P.R.Elliott, P.E.Stein, D.Bilton, R.W.Carrell, and D.A.Lomas (1996).
Structural explanation for the deficiency of S alpha 1-antitrypsin.
  Nat Struct Biol, 3, 910-911.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.