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PDBsum entry 1nq9

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protein ligands Protein-protein interface(s) links
Blood clotting PDB id
1nq9
Jmol
Contents
Protein chain
406 a.a. *
Ligands
NAG ×2
NAG-NAG ×3
NTP ×2
Waters ×89
* Residue conservation analysis
PDB id:
1nq9
Name: Blood clotting
Title: Crystal structure of antithrombin in the pentasaccharide-bou intermediate state
Structure: Antithrombin-iii. Chain: i, l. Synonym: atiii. Pro0309. Other_details: alpha glycoform
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: blood. Tissue: plasma. Other_details: alpha glycoform purified from discarded plas
Resolution:
2.60Å     R-factor:   0.209     R-free:   0.250
Authors: J.A.Huntington,D.J.D.Johnson
Key ref:
D.J.Johnson and J.A.Huntington (2003). Crystal structure of antithrombin in a heparin-bound intermediate state. Biochemistry, 42, 8712-8719. PubMed id: 12873131 DOI: 10.1021/bi034524y
Date:
21-Jan-03     Release date:   30-Sep-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01008  (ANT3_HUMAN) -  Antithrombin-III
Seq:
Struc:
464 a.a.
406 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   5 terms 
  Biological process     regulation of blood coagulation, intrinsic pathway   8 terms 
  Biochemical function     protein binding     5 terms  

 

 
DOI no: 10.1021/bi034524y Biochemistry 42:8712-8719 (2003)
PubMed id: 12873131  
 
 
Crystal structure of antithrombin in a heparin-bound intermediate state.
D.J.Johnson, J.A.Huntington.
 
  ABSTRACT  
 
Antithrombin is activated as an inhibitor of the coagulation proteases through its specific interaction with a heparin pentasaccharide. The binding of heparin induces a global conformational change in antithrombin which results in the freeing of its reactive center loop for interaction with target proteases and a 1000-fold increase in heparin affinity. The allosteric mechanism by which the properties of antithrombin are altered by its interactions with the specific pentasaccharide sequence of heparin is of great interest to the medical and protein biochemistry communities. Heparin binding has previously been characterized as a two-step, three-state mechanism where, after an initial weak interaction, antithrombin undergoes a conformational change to its high-affinity state. Although the native and heparin-activated states have been determined through protein crystallography, the number and magnitude of conformational changes render problematic the task of determining which account for the improved heparin affinity and how the heparin binding region is linked to the expulsion of the reactive center loop. Here we present the structure of an intermediate pentasaccharide-bound conformation of antithrombin which has undergone all of the conformational changes associated with activation except loop expulsion and helix D elongation. We conclude that the basis of the high-affinity state is not improved interaction with the pentasaccharide but a lowering of the global free energy due to conformational changes elsewhere in antithrombin. We suggest a mechanism in which the role of helix D elongation is to lock antithrombin in the five-stranded fully activated conformation.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20080729 D.J.Johnson, J.Langdown, and J.A.Huntington (2010).
Molecular basis of factor IXa recognition by heparin-activated antithrombin revealed by a 1.7-A structure of the ternary complex.
  Proc Natl Acad Sci U S A, 107, 645-650.
PDB code: 3kcg
19425011 A.Liang, A.Raghuraman, and U.R.Desai (2009).
Capillary electrophoretic study of small, highly sulfated, non-sugar molecules interacting with antithrombin.
  Electrophoresis, 30, 1544-1551.  
19452598 J.Langdown, K.J.Belzar, W.J.Savory, T.P.Baglin, and J.A.Huntington (2009).
The critical role of hinge-region expulsion in the induced-fit heparin binding mechanism of antithrombin.
  J Mol Biol, 386, 1278-1289.  
18845539 M.Mitsi, K.Forsten-Williams, M.Gopalakrishnan, and M.A.Nugent (2008).
A catalytic role of heparin within the extracellular matrix.
  J Biol Chem, 283, 34796-34807.  
18436534 S.H.Li, N.V.Gorlatova, D.A.Lawrence, and B.S.Schwartz (2008).
Structural differences between active forms of plasminogen activator inhibitor type 1 revealed by conformationally sensitive ligands.
  J Biol Chem, 283, 18147-18157.  
16759098 A.Raghuraman, P.D.Mosier, and U.R.Desai (2006).
Finding a needle in a haystack: development of a combinatorial virtual screening approach for identifying high specificity heparin/heparan sulfate sequence(s).
  J Med Chem, 49, 3553-3562.  
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.  
16973611 D.J.Johnson, J.Langdown, W.Li, S.A.Luis, T.P.Baglin, and J.A.Huntington (2006).
Crystal structure of monomeric native antithrombin reveals a novel reactive center loop conformation.
  J Biol Chem, 281, 35478-35486.
PDB codes: 1t1f 2b5t 2beh
16820297 J.A.Huntington (2006).
Shape-shifting serpins--advantages of a mobile mechanism.
  Trends Biochem Sci, 31, 427-435.  
16940049 R.G.dela Cruz, M.A.Jairajpuri, and S.C.Bock (2006).
Disruption of a tight cluster surrounding tyrosine 131 in the native conformation of antithrombin III activates it for factor Xa inhibition.
  J Biol Chem, 281, 31668-31676.  
15309521 M.Steiner, B.Steiner, A.Rolfs, M.Wangnick, C.Burstein, M.Freund, and P.Schuff-Werner (2005).
Antithrombin gene mutation 5356-5364*delCTT with type I deficiency and early-onset thrombophilia and a brief review of the antithrombin alpha-helix D molecular pathology.
  Ann Hematol, 84, 56-58.  
15922935 M.de Kort, R.C.Buijsman, and C.A.van Boeckel (2005).
Synthetic heparin derivatives as new anticoagulant drugs.
  Drug Discov Today, 10, 769-779.  
16094685 S.Choi, D.J.Clements, V.Pophristic, I.Ivanov, S.Vemparala, J.S.Bennett, M.L.Klein, J.D.Winkler, and W.F.DeGrado (2005).
The design and evaluation of heparin-binding foldamers.
  Angew Chem Int Ed Engl, 44, 6685-6689.  
14623882 D.J.Johnson, and J.A.Huntington (2004).
The influence of hinge region residue Glu-381 on antithrombin allostery and metastability.
  J Biol Chem, 279, 4913-4921.
PDB code: 1oyh
15326167 J.Langdown, D.J.Johnson, T.P.Baglin, and J.A.Huntington (2004).
Allosteric activation of antithrombin critically depends upon hinge region extension.
  J Biol Chem, 279, 47288-47297.  
15311269 W.Li, D.J.Johnson, C.T.Esmon, and J.A.Huntington (2004).
Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin.
  Nat Struct Mol Biol, 11, 857-862.
PDB code: 1tb6
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 code is shown on the right.