PDBsum entry 1qlp

Serine protease inhibitor

PDB id

1qlp

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Contents

			Protein chain

					372 a.a. *

			Waters ×106

* Residue conservation analysis

PDB id:

1qlp

Links

Name:

Serine protease inhibitor

Title:

2.0 angstrom structure of intact alpha-1-antitrypsin: a canonical template for active serpins

Structure:

Alpha-1-antitrypsin. Chain: a. Synonym: alpha-1-proteinase inhibitor, alpha-1-antiproteinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: liver. Tissue: hepatocytes. Cell: neutrophils. Cellular_location: cytoplasm. Gene: alpha-1-antitrypsin. Expressed in: escherichia coli.

Resolution:

2.00Å

R-factor:

0.231

R-free:

0.266

Authors:

P.R.Elliott,X.Y.Pei,T.Dafforn,R.J.Read,R.W.Carrell,D.A.Lomas

Key ref:

P.R.Elliott et al. (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. PubMed id: 10933492 DOI: 10.1110/ps.9.7.1274

Date:

10-Sep-99

Release date:

27-Sep-99

Supersedes:

2psi

PROCHECK

	Headers

	References

Protein chain

P01009 (A1AT_HUMAN) - Alpha-1-antitrypsin from Homo sapiens

Seq: Struc:					418 a.a. 372 a.a.

Key:

PfamA domain

Secondary structure

CATH domain

DOI no: 10.1110/ps.9.7.1274	Protein Sci 9:1274-1281 (2000)
PubMed id: 10933492

Topography of a 2.0 A structure of alpha1-antitrypsin reveals targets for rational drug design to prevent conformational disease.
P.R.Elliott, X.Y.Pei, T.R.Dafforn, D.A.Lomas.

ABSTRACT

Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement cascades. An inherent part of their function is the ability to undergo a structural rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A beta-sheet. In order for this transition to take place, the A sheet has to be unusually flexible. Malfunctions in this flexibility can lead to aberrant protein linkage, serpin inactivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emphysema, and dementia. The development of agents that control this conformational rearrangement requires a high resolution structure of an active serpin. We present here the topology of the archetypal serpin alpha1-antitrypsin to 2 A resolution. This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21258324

B.Krishnan, and L.M.Gierasch (2011).
Dynamic local unfolding in the serpin α-1 antitrypsin provides a mechanism for loop insertion and polymerization.

Nat Struct Mol Biol, 18, 222-226.

21383917

P.Singh, and M.A.Jairajpuri (2011).
Strand 6B deformation and residues exposure towards N-terminal end of helix B during proteinase inhibition by Serpins.

Bioinformation, 5, 315-319.

19953505

D.Belorgey, P.Hägglöf, M.Onda, and D.A.Lomas (2010).
pH-dependent stability of neuroserpin is mediated by histidines 119 and 138; implications for the control of beta-sheet A and polymerization.

Protein Sci, 19, 220-228.

19495939

E.Karnaukhova (2010).
Interactions of alpha1-proteinase inhibitor with small ligands of therapeutic potential: binding with retinoic acid.

Amino Acids, 38, 1011-1020.

20615447

P.Goettig, V.Magdolen, and H.Brandstetter (2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).

Biochimie, 92, 1546-1567.

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.

19450287

A.Stivala, A.Wirth, and P.J.Stuckey (2009).
Tableau-based protein substructure search using quadratic programming.

BMC Bioinformatics, 10, 153.

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

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.

19172319

V.Chandrasekaran, C.J.Lee, P.Lin, R.E.Duke, and L.G.Pedersen (2009).
A computational modeling and molecular dynamics study of the Michaelis complex of human protein Z-dependent protease inhibitor (ZPI) and factor Xa (FXa).

J Mol Model, 15, 897-911.

18780818

M.C.Pearce, C.J.Morton, S.C.Feil, G.Hansen, J.J.Adams, M.W.Parker, and S.P.Bottomley (2008).
Preventing serpin aggregation: the molecular mechanism of citrate action upon antitrypsin unfolding.

Protein Sci, 17, 2127-2133.

PDB codes:

2qug 3cwl 3cwm

18184582

X.Zheng, P.L.Wintrode, and M.R.Chance (2008).
Complementary structural mass spectrometry techniques reveal local dynamics in functionally important regions of a metastable serpin.

Structure, 16, 38-51.

19164889

D.Belorgey, P.Hägglöf, S.Karlsson-Li, and D.A.Lomas (2007).
Protein misfolding and the serpinopathies.

Prion, 1, 15-20.

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.

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.

16820297

J.A.Huntington (2006).
Shape-shifting serpins--advantages of a mobile mechanism.

Trends Biochem Sci, 31, 427-435.

16231289

H.Li, A.D.Robertson, and J.H.Jensen (2005).
Very fast empirical prediction and rationalization of protein pKa values.

Proteins, 61, 704-721.

15695806

Y.Tong, H.Jiang, and M.R.Kanost (2005).
Identification of plasma proteases inhibited by Manduca sexta serpin-4 and serpin-5 and their association with components of the prophenol oxidase activation pathway.

J Biol Chem, 280, 14932-14942.

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.

15569049

R.Aldonyte, L.Jansson, O.Ljungberg, S.Larsson, and S.Janciauskiene (2004).
Polymerized alpha-antitrypsin is present on lung vascular endothelium. New insights into the biological significance of alpha-antitrypsin polymerization.

Histopathology, 45, 587-592.

15050036

R.Aldonyte, L.Jansson, and S.Janciauskiene (2004).
Concentration-dependent effects of native and polymerised alpha1-antitrypsin on primary human monocytes, in vitro.

BMC Cell Biol, 5, 11.

15486938

S.Janciauskiene, S.Eriksson, F.Callea, M.Mallya, A.Zhou, K.Seyama, S.Hata, and D.A.Lomas (2004).
Differential detection of PAS-positive inclusions formed by the Z, Siiyama, and Mmalton variants of alpha1-antitrypsin.

Hepatology, 40, 1203-1210.

12871373

D.Naessens, A.Gils, G.Compernolle, and P.J.Declerck (2003).
Elucidation of a novel epitope of a substrate-inducing monoclonal antibody against the serpin PAI-1.

J Thromb Haemost, 1, 1028-1033.

12682008

M.Wilczynska, S.Lobov, P.I.Ohlsson, and T.Ny (2003).
A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization.

EMBO J, 22, 1753-1761.

12694181

T.Wind, J.K.Jensen, D.M.Dupont, P.Kulig, and P.A.Andreasen (2003).
Mutational analysis of plasminogen activator inhibitor-1.

Eur J Biochem, 270, 1680-1688.

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.

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.

11928815

T.Wind, M.Hansen, J.K.Jensen, and P.A.Andreasen (2002).
The molecular basis for anti-proteolytic and non-proteolytic functions of plasminogen activator inhibitor type-1: roles of the reactive centre loop, the shutter region, the flexible joint region and the small serpin fragment.

Biol Chem, 383, 21-36.

11420185

R.A.Primhak, and M.S.Tanner (2001).
Alpha-1 antitrypsin deficiency.

Arch Dis Child, 85, 2-5.

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.