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PDBsum entry 1sr5
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Hydrolase/hydrolase inhibitor PDB id
1sr5

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
409 a.a. *
32 a.a. *
248 a.a. *
Ligands
YYB-U9J-GU6-U9M-
U9G-GU8-U9D
NAG ×3
GU4
Waters ×75
* Residue conservation analysis
PDB id:
1sr5
Name: Hydrolase/hydrolase inhibitor
Title: Antithrombin-anhydrothrombin-heparin ternary complex structure
Structure: Antithrombin-iii. Chain: a. Synonym: atiii, pro0309. Prothrombin. Chain: b. Fragment: light chain (residues 328-363). Synonym: coagulation factor ii. Prothrombin. Chain: c.
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: plasma. Tissue: plasma
Biol. unit: Trimer (from PQS)
Resolution:
3.10Å     R-factor:   0.227     R-free:   0.278
Authors: A.Dementiev,M.Petitou,P.G.Gettins
Key ref:
A.Dementiev et al. (2004). The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity. Nat Struct Mol Biol, 11, 863-867. PubMed id: 15311268 DOI: 10.1038/nsmb810
Date:
22-Mar-04     Release date:   17-Aug-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01008  (ANT3_HUMAN) -  Antithrombin-III from Homo sapiens
Seq:
Struc: 		464 a.a.
409 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
32 a.a.
Protein chain
Pfam   ArchSchema ?
P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		622 a.a.
248 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains B, C: E.C.3.4.21.5  - thrombin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

 

 
DOI no: 10.1038/nsmb810 Nat Struct Mol Biol 11:863-867 (2004)
PubMed id: 15311268  
 
 
The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity.
A.Dementiev, M.Petitou, J.M.Herbert, P.G.Gettins.
 
  ABSTRACT  
 
Antithrombin, the principal physiological inhibitor of the blood coagulation proteinase thrombin, requires heparin as a cofactor. We report the crystal structure of the rate-determining encounter complex formed between antithrombin, anhydrothrombin and an optimal synthetic 16-mer oligosaccharide. The antithrombin reactive center loop projects from the serpin body and adopts a canonical conformation that makes extensive backbone and side chain contacts from P5 to P6' with thrombin's restrictive specificity pockets, including residues in the 60-loop. These contacts rationalize many earlier mutagenesis studies on thrombin specificity. The 16-mer oligosaccharide is just long enough to form the predicted bridge between the high-affinity pentasaccharide-binding site on antithrombin and the highly basic exosite 2 on thrombin, validating the design strategy for this synthetic heparin. The protein-protein and protein-oligosaccharide interactions together explain the basis for heparin activation of antithrombin as a thrombin inhibitor.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Stereo ribbon representation of the ternary complex. Antithrombin is gold, with the exception of the reactive center loop (cyan). Thrombin is red and the 16-mer heparin is in stick form, with those residues that are visible in the electron density in black and those that are modeled in green. 		Figure 3.
Figure 3. The antithrombin reactive center loop conformation and contacts with thrombin. (a) Stereo view of the antithrombin RCL from P7 to P6' (ball and stick) interacting with the surface of thrombin portrayed using GRASP. The residues P7 to P6' are Ala-Val-Val-Ile-Ala-Gly-Arg-Ser-Leu-Asn-Pro-Asn (the scissile P1-P1' residues are underlined). (b) Stereo view of contacts between the antithrombin RCL from P7 to P6' (cyan) and residues in and around the thrombin active site (green), using a transparent view of the thrombin surface (gray). The orientation is the same in both views.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2004, 11, 863-867) copyright 2004.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20594934 E.Fadda, and R.J.Woods (2010).
Molecular simulations of carbohydrates and protein-carbohydrate interactions: motivation, issues and prospects.
  Drug Discov Today, 15, 596-609.  
21062218 L.Muszbek, Z.Bereczky, B.Kovács, and I.Komáromi (2010).
Antithrombin deficiency and its laboratory diagnosis.
  Clin Chem Lab Med, 48, S67-S78.  
20207734 M.Bekhouche, D.Kronenberg, S.Vadon-Le Goff, C.Bijakowski, N.H.Lim, B.Font, E.Kessler, A.Colige, H.Nagase, G.Murphy, D.J.Hulmes, and C.Moali (2010).
Role of the netrin-like domain of procollagen C-proteinase enhancer-1 in the control of metalloproteinase activity.
  J Biol Chem, 285, 15950-15959.  
20615447 P.Goettig, V.Magdolen, and H.Brandstetter (2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).
  Biochimie, 92, 1546-1567.  
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.  
19144372 J.O'Donnell, K.A.Taylor, and M.S.Chapman (2009).
Adeno-associated virus-2 and its primary cellular receptor--Cryo-EM structure of a heparin complex.
  Virology, 385, 434-443.  
19178150 L.Yang, M.F.Sun, D.Gailani, and A.R.Rezaie (2009).
Characterization of a heparin-binding site on the catalytic domain of factor XIa: mechanism of heparin acceleration of factor XIa inhibition by the serpins antithrombin and C1-inhibitor.
  Biochemistry, 48, 1517-1524.  
19401470 P.G.Gettins, and S.T.Olson (2009).
Exosite determinants of serpin specificity.
  J Biol Chem, 284, 20441-20445.  
18375953 B.Richard, R.Swanson, S.Schedin-Weiss, B.Ramirez, G.Izaguirre, P.G.Gettins, and S.T.Olson (2008).
Characterization of the conformational alterations, reduced anticoagulant activity, and enhanced antiangiogenic activity of prelatent antithrombin.
  J Biol Chem, 283, 14417-14429.  
18329094 E.Di Cera (2008).
Thrombin.
  Mol Aspects Med, 29, 203-254.  
18065761 K.Tan, M.Duquette, J.H.Liu, K.Shanmugasundaram, A.Joachimiak, J.T.Gallagher, A.C.Rigby, J.H.Wang, and J.Lawler (2008).
Heparin-induced cis- and trans-dimerization modes of the thrombospondin-1 N-terminal domain.
  J Biol Chem, 283, 3932-3941.
PDB codes: 2es3 2ouh 2ouj
18971322 S.B.Long, M.B.Long, R.R.White, and B.A.Sullenger (2008).
Crystal structure of an RNA aptamer bound to thrombin.
  RNA, 14, 2504-2512.
PDB code: 3dd2
18060440 T.H.Roberts, and J.Hejgaard (2008).
Serpins in plants and green algae.
  Funct Integr Genomics, 8, 1.  
17347701 E.Di Cera, M.J.Page, A.Bah, L.A.Bush-Pelc, and L.C.Garvey (2007).
Thrombin allostery.
  Phys Chem Chem Phys, 9, 1291-1306.  
17875649 G.Izaguirre, R.Swanson, S.M.Raja, A.R.Rezaie, and S.T.Olson (2007).
Mechanism by which exosites promote the inhibition of blood coagulation proteases by heparin-activated antithrombin.
  J Biol Chem, 282, 33609-33622.  
17635716 J.C.Rau, L.M.Beaulieu, J.A.Huntington, and F.C.Church (2007).
Serpins in thrombosis, hemostasis and fibrinolysis.
  J Thromb Haemost, 5, 102-115.  
17131147 J.Liu, and L.C.Pedersen (2007).
Anticoagulant heparan sulfate: structural specificity and biosynthesis.
  Appl Microbiol Biotechnol, 74, 263-272.  
17488724 L.Beinrohr, V.Harmat, J.Dobó, Z.Lörincz, P.Gál, and P.Závodszky (2007).
C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease.
  J Biol Chem, 282, 21100-21109.
PDB code: 2oay
17905675 P.R.Gonzales, T.D.Walston, L.O.Camacho, D.M.Kielar, F.C.Church, A.R.Rezaie, and S.T.Cooper (2007).
Mutation of the H-helix in antithrombin decreases heparin stimulation of protease inhibition.
  Biochim Biophys Acta, 1774, 1431-1437.  
17145752 S.Glerup, S.Kløverpris, L.S.Laursen, F.Dagnaes-Hansen, S.Thiel, C.A.Conover, and C.Oxvig (2007).
Cell surface detachment of pregnancy-associated plasma protein-A requires the formation of intermolecular proteinase-inhibitor disulfide bonds and glycosaminoglycan covalently bound to the inhibitor.
  J Biol Chem, 282, 1769-1778.  
17088529 A.Beenken, and M.Mohammadi (2006).
Hedgehogs like it sweet, too.
  Proc Natl Acad Sci U S A, 103, 17069-17070.  
16321984 A.Dementiev, J.Dobó, and P.G.Gettins (2006).
Active site distortion is sufficient for proteinase inhibition by serpins: structure of the covalent complex of alpha1-proteinase inhibitor with porcine pancreatic elastase.
  J Biol Chem, 281, 3452-3457.
PDB code: 2d26
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.  
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
16619025 D.J.Johnson, W.Li, T.E.Adams, and J.A.Huntington (2006).
Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation.
  EMBO J, 25, 2029-2037.
PDB code: 2gd4
16517611 G.Izaguirre, and S.T.Olson (2006).
Residues Tyr253 and Glu255 in strand 3 of beta-sheet C of antithrombin are key determinants of an exosite made accessible by heparin activation to promote rapid inhibition of factors Xa and IXa.
  J Biol Chem, 281, 13424-13432.  
16820297 J.A.Huntington (2006).
Shape-shifting serpins--advantages of a mobile mechanism.
  Trends Biochem Sci, 31, 427-435.  
17042782 S.Skeldal, J.V.Larsen, K.E.Pedersen, H.H.Petersen, R.Egelund, A.Christensen, J.K.Jensen, J.Gliemann, and P.A.Andreasen (2006).
Binding areas of urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex for endocytosis receptors of the low-density lipoprotein receptor family, determined by site-directed mutagenesis.
  FEBS J, 273, 5143-5159.  
15590653 K.F.Fulton, A.M.Buckle, L.D.Cabrita, J.A.Irving, R.E.Butcher, I.Smith, S.Reeve, A.M.Lesk, S.P.Bottomley, J.Rossjohn, and J.C.Whisstock (2005).
The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition.
  J Biol Chem, 280, 8435-8442.
PDB code: 1sng
15851487 K.Ingold, A.Zumsteg, A.Tardivel, B.Huard, Q.G.Steiner, T.G.Cachero, F.Qiang, L.Gorelik, S.L.Kalled, H.Acha-Orbea, P.D.Rennert, J.Tschopp, and P.Schneider (2005).
Identification of proteoglycans as the APRIL-specific binding partners.
  J Exp Med, 201, 1375-1383.  
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.  
16176258 R.N.Pike, A.M.Buckle, B.F.le Bonniec, and F.C.Church (2005).
Control of the coagulation system by serpins. Getting by with a little help from glycosaminoglycans.
  FEBS J, 272, 4842-4851.  
15892855 W.Bode (2005).
The structure of thrombin, a chameleon-like proteinase.
  J Thromb Haemost, 3, 2379-2388.  
15548541 W.J.Carter, E.Cama, and J.A.Huntington (2005).
Crystal structure of thrombin bound to heparin.
  J Biol Chem, 280, 2745-2749.
PDB code: 1xmn
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.

 

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