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PDBsum entry 1qmn

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protein links
Hydrolase inhibitor PDB id
1qmn
Jmol
Contents
Protein chain
365 a.a. *
* Residue conservation analysis
PDB id:
1qmn
Name: Hydrolase inhibitor
Title: Alpha1-antichymotrypsin serpin in the delta conformation (partial loop insertion)
Structure: Alpha-1-antichymotrypsin. Chain: a. Synonym: aact, act, cell growth-inhibiting gene 24/25 prote serpin a3, alpha-1-antichymotrypsin his-pro-less. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood plasma. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: the mutation is a naturally occurring variant
Resolution:
2.27Å     R-factor:   0.197     R-free:   0.243
Authors: B.Gooptu,B.Hazes,D.A.Lomas
Key ref:
B.Gooptu et al. (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. PubMed id: 10618372 DOI: 10.1073/pnas.97.1.67
Date:
04-Oct-99     Release date:   17-Jan-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01011  (AACT_HUMAN) -  Alpha-1-antichymotrypsin
Seq:
Struc:
423 a.a.
365 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   6 terms 
  Biological process     inflammatory response   7 terms 
  Biochemical function     protein binding     4 terms  

 

 
DOI no: 10.1073/pnas.97.1.67 Proc Natl Acad Sci U S A 97:67-72 (2000)
PubMed id: 10618372  
 
 
Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease.
B.Gooptu, B.Hazes, W.S.Chang, T.R.Dafforn, R.W.Carrell, R.J.Read, D.A.Lomas.
 
  ABSTRACT  
 
The serpins are a family of proteinase inhibitors that play a central role in the control of proteolytic cascades. Their inhibitory mechanism depends on the intramolecular insertion of the reactive loop into beta-sheet A after cleavage by the target proteinase. Point mutations within the protein can allow aberrant conformational transitions characterized by beta-strand exchange between the reactive loop of one molecule and beta-sheet A of another. These loop-sheet polymers result in diseases as varied as cirrhosis, emphysema, angio-oedema, and thrombosis, and we recently have shown that they underlie an early-onset dementia. We report here the biochemical characteristics and crystal structure of a naturally occurring variant (Leu-55-Pro) of the plasma serpin alpha(1)-antichymotrypsin trapped as an inactive intermediate. The structure demonstrates a serpin configuration with partial insertion of the reactive loop into beta-sheet A. The lower part of the sheet is filled by the last turn of F-helix and the loop that links it to s3A. This conformation matches that of proposed intermediates on the pathway to complex and polymer formation in the serpins. In particular, this intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma alpha(1)-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55-Pro mutation.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Schematic diagram showing the diffraction data characteristics as a function of resolution. The data completeness drops off sharply beyond 2.5 Å as a result of radiation decay, but the higher-resolution reflections are still useful as indicated by the signal-to-noise ratio. In total 18,805 reflections were measured, yielding 11,373 unique observations between 41.0 and 2.3 Å. The overall multiplicity-weighted R[merge] (43) is 13.1%, increasing to 48.5% in the highest-resolution shell.
Figure 3.
Fig. 3. (a) Structure of Leu-55-Pro [1]-antichymotrypsin showing the reactive loop in red, the A-sheet in green, and the F-helix in yellow. Asn-163, whose side chain mimics the peptide plane in position P[11] of s4A, is shown in ball-and-stick representation. Residues 353-357 (P[6]-P[2]) could not be built and are illustrated as a broken black line. The gate region including s3C and s4C, over which the loop must pass to form the latent conformation, is indicated. The shutter domain underlying the opening of the A-sheet is shown, together with (in black) the five residues at its focus at the s6B-hB junction (Inset). The Leu-55-Pro mutation is shown in red with, in blue, six other mutations that result in serpin polymerization and diseases as diverse as cirrhosis, thrombosis, angio-oedema, and dementia. (b) Cleaved reactive loop of [1]-antichymotrypsin in black (20) with final model of Leu-55-Pro [1]-antichymotrypsin shown in yellow. The SIGMAA-weighted 2F[o]-F[c] (purple) and F[o]-F[c] (pink) electron density maps are shown before rebuilding the molecular replacement model. The break in s4A (between P[12] and P[10]), the connection to helix F at P[10], and the density as the loop leaves the A-sheet at position 12 are clearly visible. Clear F[o]-F[c] density (pink) at position P[7] indicates the presence of Arg-166. (c) -sheet C from Leu-55-Pro [1]-antichymotrypsin (white) superimposed on reactive loop cleaved [1]-antichymotrypsin (black) showing displacement of the main-chain residues of s1C. (d) Schematic illustration of conformational transitions of the serpins. The active serpin (M) has an exposed reactive center loop (red) similar to that of [1]-antitrypsin (30). After activation by heat or destabilizing mutations in the shutter domain (red circle) there is opening of -sheet A and reactive loop insertion to P[12]. This state, computationally modeled as a chimera between and cleaved [1]-antichymotrypsin, is illustrated as M*. The A-sheet can receive the loop of another molecule (black dotted arrow) to form a loop-sheet dimer (P) and then extend to form a chain of polymers. Alternatively if there is sufficient energy to displace s1C the serpin loop can fully insert to form the latent conformation (L) (29). Leu-55-Pro [1]-antichymotrypsin represents a third conformation in which the open A-sheet is filled by insertion of an unfolded loop of the F-helix (yellow). The figures were prepared with MOLSCRIPT (44).
 
  Figures were selected by an automated process.  

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.  
20731544 J.A.Huntington, and J.C.Whisstock (2010).
Molecular contortionism - on the physical limits of serpin 'loop-sheet' polymers.
  Biol Chem, 391, 973-982.  
21081089 S.Ricagno, M.Pezzullo, A.Barbiroli, M.Manno, M.Levantino, M.G.Santangelo, F.Bonomi, and M.Bolognesi (2010).
Two latent and two hyperstable polymeric forms of human neuroserpin.
  Biophys J, 99, 3402-3411.  
20855577 U.I.Ekeowa, J.Freeke, E.Miranda, B.Gooptu, M.F.Bush, J.Pérez, J.Teckman, C.V.Robinson, and D.A.Lomas (2010).
Defining the mechanism of polymerization in the serpinopathies.
  Proc Natl Acad Sci U S A, 107, 17146-17151.  
18785256 A.S.Knaupp, and S.P.Bottomley (2009).
Serpin polymerization and its role in disease--the molecular basis of alpha1-antitrypsin deficiency.
  IUBMB Life, 61, 1-5.  
19245336 B.Gooptu, and D.A.Lomas (2009).
Conformational pathology of the serpins: themes, variations, and therapeutic strategies.
  Annu Rev Biochem, 78, 147-176.  
19232354 B.Gooptu, E.Miranda, I.Nobeli, M.Mallya, A.Purkiss, S.C.Brown, C.Summers, R.L.Phillips, D.A.Lomas, and T.E.Barrett (2009).
Crystallographic and cellular characterisation of two mechanisms stabilising the native fold of alpha1-antitrypsin: implications for disease and drug design.
  J Mol Biol, 387, 857-868.
PDB codes: 3drm 3dru
19136720 J.H.Baek, W.S.Yang, C.Lee, and M.H.Yu (2009).
Functional unfolding of alpha1-antitrypsin probed by hydrogen-deuterium exchange coupled with mass spectrometry.
  Mol Cell Proteomics, 8, 1072-1081.  
19423713 M.J.Davies, E.Miranda, B.D.Roussel, R.J.Kaufman, S.J.Marciniak, and D.A.Lomas (2009).
Neuroserpin polymers activate NF-kappaB by a calcium signaling pathway that is independent of the unfolded protein response.
  J Biol Chem, 284, 18202-18209.  
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.  
18729044 C.H.Chu, C.Y.Tang, C.Y.Tang, and T.W.Pai (2008).
Angle-distance image matching techniques for protein structure comparison.
  J Mol Recognit, 21, 442-452.  
18794298 Y.Tsutsui, B.Kuri, T.Sengupta, and P.L.Wintrode (2008).
The structural basis of serpin polymerization studied by hydrogen/deuterium exchange and mass spectrometry.
  J Biol Chem, 283, 30804-30811.  
18005453 A.Abyzov, and V.A.Ilyin (2007).
A comprehensive analysis of non-sequential alignments between all protein structures.
  BMC Struct Biol, 7, 78.  
17660256 J.H.Baek, H.Im, U.B.Kang, K.M.Seong, C.Lee, J.Kim, and M.H.Yu (2007).
Probing the local conformational change of alpha1-antitrypsin.
  Protein Sci, 16, 1842-1850.  
17918823 M.Mallya, R.L.Phillips, S.A.Saldanha, B.Gooptu, S.C.Brown, D.J.Termine, A.M.Shirvani, Y.Wu, R.N.Sifers, R.Abagyan, and D.A.Lomas (2007).
Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates.
  J Med Chem, 50, 5357-5363.  
16938877 A.Zhou, Z.Wei, R.J.Read, and R.W.Carrell (2006).
Structural mechanism for the carriage and release of thyroxine in the blood.
  Proc Natl Acad Sci U S A, 103, 13321-13326.
PDB code: 2ceo
16921127 D.A.Lomas (2006).
Parker B. Francis lectureship. Antitrypsin deficiency, the serpinopathies, and chronic obstructive pulmonary disease.
  Proc Am Thorac Soc, 3, 499-501.  
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.  
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.  
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.  
14668352 B.Kroczynska, C.M.Evangelista, S.S.Samant, E.C.Elguindi, and S.Y.Blond (2004).
The SANT2 domain of the murine tumor cell DnaJ-like protein 1 human homologue interacts with alpha1-antichymotrypsin and kinetically interferes with its serpin inhibitory activity.
  J Biol Chem, 279, 11432-11443.  
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.  
15291813 D.Belorgey, L.K.Sharp, D.C.Crowther, M.Onda, J.Johansson, and D.A.Lomas (2004).
Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB.
  Eur J Biochem, 271, 3360-3367.  
  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.  
12112652 D.C.Crowther (2002).
Familial conformational diseases and dementias.
  Hum Mutat, 20, 1.  
11686861 D.A.Lomas, and E.K.Silverman (2001).
The genetics of chronic obstructive pulmonary disease.
  Respir Res, 2, 20-26.  
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.  
11473647 M.Nangaku, T.Miyata, D.Suzuki, T.Umezono, T.Hashimoto, T.Wada, M.Yagi, N.Nagano, R.Inagi, and K.Kurokawa (2001).
Cloning of rodent megsin revealed its up-regulation in mesangioproliferative nephritis.
  Kidney Int, 60, 641-652.  
11278163 S.Janciauskiene (2001).
Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles.
  Biochim Biophys Acta, 1535, 221-235.  
11179902 S.Sunyaev, W.Lathe, and P.Bork (2001).
Integration of genome data and protein structures: prediction of protein folds, protein interactions and "molecular phenotypes" of single nucleotide polymorphisms.
  Curr Opin Struct Biol, 11, 125-130.  
11004579 I.Simonovic, and P.A.Patston (2000).
The native metastable fold of C1-inhibitor is stabilized by disulfide bonds.
  Biochim Biophys Acta, 1481, 97.  
  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
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.