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PDBsum entry 1fax

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Coagulation factor PDB id
1fax

 

 

 

 

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Contents
Protein chains
235 a.a. *
55 a.a. *
Ligands
DX9
Metals
_CA
* Residue conservation analysis
PDB id:
1fax
Name: Coagulation factor
Title: Coagulation factor xa inhibitor complex
Structure: Factor xa. Chain: a. Synonym: stuart factor. Engineered: yes. Mutation: yes. Factor xa. Chain: l. Synonym: stuart factor. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Tissue: blood
Biol. unit: Dimer (from PQS)
Resolution:
3.00Å     R-factor:   0.197     R-free:   0.261
Authors: H.Brandstetter,R.A.Engh
Key ref:
H.Brandstetter et al. (1996). X-ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition. J Biol Chem, 271, 29988-29992. PubMed id: 8939944 DOI: 10.1074/jbc.271.47.29988
Date:
23-Aug-96     Release date:   29-Oct-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens
Seq:
Struc:
488 a.a.
235 a.a.*
Protein chain
Pfam   ArchSchema ?
P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens
Seq:
Struc:
488 a.a.
55 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, L: E.C.3.4.21.6  - coagulation factor Xa.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

 

 
DOI no: 10.1074/jbc.271.47.29988 J Biol Chem 271:29988-29992 (1996)
PubMed id: 8939944  
 
 
X-ray structure of active site-inhibited clotting factor Xa. Implications for drug design and substrate recognition.
H.Brandstetter, A.Kühne, W.Bode, R.Huber, W.von der Saal, K.Wirthensohn, R.A.Engh.
 
  ABSTRACT  
 
The 3.0-A resolution x-ray structure of human des-Gla-coagulation factor Xa (fXa) has been determined in complex with the synthetic inhibitor DX-9065a. The binding geometry is characterized primarily by two interaction sites: the naphthamidine group is fixed in the S1 pocket by a typical salt bridge to Asp-189, while the pyrrolidine ring binds in the unique aryl-binding site (S4) of fXa. Unlike the large majority of inhibitor complexes with serine proteinases, Gly-216 (S3) does not contribute to hydrogen bond formation. In contrast to typical thrombin binding modes, the S2 site of fXa cannot be used by DX-9065a since it is blocked by Tyr-99, and the aryl-binding site (S4) of fXa is lined by carbonyl oxygen atoms that can accommodate positive charges. This has implications for natural substrate recognition as well as for drug design.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Chemical formula of the DX-9065a inhibitor: (2S)-{4-[1-acetimidoyl-(3S)-pyrrolidinyl]-oxyphenyl}-3-(7-amidino-2-naphthyl)propionic^ acid hydrochloride pentahydrate.
Figure 3.
Fig. 3. Binding interactions of DX-9065a with fXa. The C^ plot and side chains involved in inhibitor binding of DX-9065a-bound^ fXa (yellow) are superimposed with the corresponding atoms of^ arginine-bound fXa (turquoise). The ligand-induced structural changes at the S1-binding site may be seen at the side chain of^ Asp-189 and along the main chain at Gln-192. The hydrophobic sleeve^ at the aryl-binding site (S4) is also apparent, with the cation hole formed by Glu-97 and the carbonyl oxygens of Glu-97 and Lys-96^ at the back.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (1996, 271, 29988-29992) copyright 1996.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20972772 V.Castro-López, L.F.Harris, J.S.O'Donnell, and A.J.Killard (2011).
Comparative study of Factor Xa fluorogenic substrates and their influence on the quantification of LMWHs.
  Anal Bioanal Chem, 399, 691-700.  
19967784 Y.K.Lee, and M.R.Player (2011).
Developments in factor Xa inhibitors for the treatment of thromboembolic disorders.
  Med Res Rev, 31, 202-283.  
20022942 S.K.Buddai, J.M.Layzer, G.Lu, C.P.Rusconi, B.A.Sullenger, D.M.Monroe, and S.Krishnaswamy (2010).
An anticoagulant RNA aptamer that inhibits proteinase-cofactor interactions within prothrombinase.
  J Biol Chem, 285, 5212-5223.  
19845314 H.Fan, J.J.Irwin, B.M.Webb, G.Klebe, B.K.Shoichet, and A.Sali (2009).
Molecular docking screens using comparative models of proteins.
  J Chem Inf Model, 49, 2512-2527.  
19656280 R.Hartmann, M.Dockal, W.Kammlander, E.Panholzer, G.A.Nicolaes, C.Fiedler, J.Rosing, and F.Scheiflinger (2009).
Factor IX mutants with enhanced catalytic activity.
  J Thromb Haemost, 7, 1656-1662.  
19361276 T.Zögg, and H.Brandstetter (2009).
Activation mechanisms of coagulation factor IX.
  Biol Chem, 390, 391-400.  
20004170 T.Zögg, and H.Brandstetter (2009).
Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa.
  Structure, 17, 1669-1678.
PDB codes: 2wph 2wpi 2wpj 2wpk 2wpl 2wpm
  19887032 Y.Chen, S.Qin, W.Tan, Y.Lu, J.Zhang, H.Li, H.Bu, and J.Cheng (2009).
Cloning and comparison of factor X from rhesus monkey (Macaca mulatta).
  Comp Med, 59, 476-481.  
18974075 C.T.Chen, E.W.Yang, H.J.Hsu, Y.K.Sun, W.L.Hsu, and A.S.Yang (2008).
Protease substrate site predictors derived from machine learning on multilevel substrate phage display data.
  Bioinformatics, 24, 2691-2697.  
18204980 D.Reid, B.S.Sadjad, Z.Zsoldos, and A.Simon (2008).
LASSO-ligand activity by surface similarity order: a new tool for ligand based virtual screening.
  J Comput Aided Mol Des, 22, 479-487.  
18296445 H.J.Hsu, K.C.Tsai, Y.K.Sun, H.J.Chang, Y.J.Huang, H.M.Yu, C.H.Lin, S.S.Mao, and A.S.Yang (2008).
Factor Xa active site substrate specificity with substrate phage display and computational molecular modeling.
  J Biol Chem, 283, 12343-12353.  
18680100 N.Singh, and J.M.Briggs (2008).
Molecular dynamics simulations of Factor Xa: insight into conformational transition of its binding subsites.
  Biopolymers, 89, 1104-1113.  
18266362 R.Abel, T.Young, R.Farid, B.J.Berne, and R.A.Friesner (2008).
Role of the active-site solvent in the thermodynamics of factor Xa ligand binding.
  J Am Chem Soc, 130, 2817-2831.  
17191291 A.Di Fenza, A.Heine, U.Koert, and G.Klebe (2007).
Understanding Binding Selectivity toward Trypsin and Factor Xa: the Role of Aromatic Interactions.
  ChemMedChem, 2, 297-308.
PDB codes: 1y59 1y5a 1y5b 1y5u
17917295 T.Noguchi, N.Tanaka, T.Nishimata, R.Goto, M.Hayakawa, A.Sugidachi, T.Ogawa, F.Asai, and K.Fujimoto (2007).
Cinnamylindoline derivatives: synthesis and factor Xa (FXa) inhibitory activities.
  Chem Pharm Bull (Tokyo), 55, 1494-1504.  
17031535 C.Williams (2006).
Reverse fingerprinting, similarity searching by group fusion and fingerprint bit importance.
  Mol Divers, 10, 311-332.  
16575920 D.N.Gosalia, W.S.Denney, C.M.Salisbury, J.A.Ellman, and S.L.Diamond (2006).
Functional phenotyping of human plasma using a 361-fluorogenic substrate biosensing microarray.
  Biotechnol Bioeng, 94, 1099-1110.  
17115712 D.Zhang, and I.M.Kovach (2006).
Deuterium solvent isotope effect and proton-inventory studies of factor Xa-catalyzed reactions.
  Biochemistry, 45, 14175-14182.  
16923021 K.M.Bromfield, N.S.Quinsey, P.J.Duggan, and R.N.Pike (2006).
Approaches to selective peptidic inhibitors of factor Xa.
  Chem Biol Drug Des, 68, 11-19.  
16437549 L.Autin, M.Steen, B.Dahlbäck, and B.O.Villoutreix (2006).
Proposed structural models of the prothrombinase (FXa-FVa) complex.
  Proteins, 63, 440-450.  
16795022 N.Murayama, M.Nakaoka, and K.Sudo (2006).
Contribution of lysosomes to concentrative uptake of DX-9065a into rat liver.
  J Pharm Sci, 95, 1763-1770.  
16462058 T.Noguchi, N.Tanaka, T.Nishimata, R.Goto, M.Hayakawa, A.Sugidachi, T.Ogawa, F.Asai, Y.Matsui, and K.Fujimoto (2006).
Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities.
  Chem Pharm Bull (Tokyo), 54, 163-174.  
15742319 D.N.Gosalia, C.M.Salisbury, D.J.Maly, J.A.Ellman, and S.L.Diamond (2005).
Profiling serine protease substrate specificity with solution phase fluorogenic peptide microarrays.
  Proteomics, 5, 1292-1298.  
16156684 J.H.Alexander, and K.P.Singh (2005).
Inhibition of Factor Xa : a potential target for the development of new anticoagulants.
  Am J Cardiovasc Drugs, 5, 279-290.  
15911309 S.Komoriya, N.Haginoya, S.Kobayashi, T.Nagata, A.Mochizuki, M.Suzuki, T.Yoshino, H.Horino, T.Nagahara, M.Suzuki, Y.Isobe, and T.Furugoori (2005).
Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites.
  Bioorg Med Chem, 13, 3927-3954.
PDB codes: 1wu1 2d1j
15634266 S.Krishnaswamy (2005).
Exosite-driven substrate specificity and function in coagulation.
  J Thromb Haemost, 3, 54-67.  
15892855 W.Bode (2005).
The structure of thrombin, a chameleon-like proteinase.
  J Thromb Haemost, 3, 2379-2388.  
15250038 C.A.Kontogiorgis, and D.Hadjipavlou-Litina (2004).
Current trends in quantitative structure activity relationships on FXa inhibitors: evaluation and comparative analysis.
  Med Res Rev, 24, 687-747.  
12814644 B.R.Lentz (2003).
Exposure of platelet membrane phosphatidylserine regulates blood coagulation.
  Prog Lipid Res, 42, 423-438.  
14579355 B.V.Norledge, R.J.Petrovan, W.Ruf, and A.J.Olson (2003).
The tissue factor/factor VIIa/factor Xa complex: a model built by docking and site-directed mutagenesis.
  Proteins, 53, 640-648.
PDB code: 1nl8
12479872 J.P.Ludeman, R.N.Pike, K.M.Bromfield, P.J.Duggan, J.Cianci, B.Le Bonniec, J.C.Whisstock, and S.P.Bottomley (2003).
Determination of the P1', P2' and P3' subsite-specificity of factor Xa.
  Int J Biochem Cell Biol, 35, 221-225.  
12787023 K.Carlsson, P.O.Freskgård, E.Persson, U.Carlsson, and M.Svensson (2003).
Probing the interface between factor Xa and tissue factor in the quaternary complex tissue factor-factor VIIa-factor Xa-tissue factor pathway inhibitor.
  Eur J Biochem, 270, 2576-2582.  
14596625 L.A.O'Brien, A.R.Stafford, J.C.Fredenburgh, and J.I.Weitz (2003).
Glycosaminoglycans bind factor Xa in a Ca2+-dependent fashion and modulate its catalytic activity.
  Biochemistry, 42, 13091-13098.  
12871539 S.S.Ahmad, F.S.London, and P.N.Walsh (2003).
The assembly of the factor X-activating complex on activated human platelets.
  J Thromb Haemost, 1, 48-59.  
12834348 S.X.Wang, E.Hur, C.A.Sousa, L.Brinen, E.J.Slivka, and R.J.Fletterick (2003).
The extended interactions and Gla domain of blood coagulation factor Xa.
  Biochemistry, 42, 7959-7966.
PDB code: 1p0s
12437122 D.Rauh, S.Reyda, G.Klebe, and M.T.Stubbs (2002).
Trypsin mutants for structure-based drug design: expression, refolding and crystallisation.
  Biol Chem, 383, 1309-1314.  
11867437 D.Venkateswarlu, L.Perera, T.Darden, and L.G.Pedersen (2002).
Structure and dynamics of zymogen human blood coagulation factor X.
  Biophys J, 82, 1190-1206.  
12237534 H.Nishida, Y.Miyazaki, T.Mukaihira, F.Saitoh, M.Fukui, K.Harada, M.Itoh, A.Muraoka, T.Matsusue, A.Okamoto, Y.Hosaka, M.Matsumoto, S.Ohnishi, and H.Mochizuki (2002).
Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities.
  Chem Pharm Bull (Tokyo), 50, 1187-1194.  
12437104 M.M.Mueller, S.Sperl, J.Stürzebecher, W.Bode, and L.Moroder (2002).
(R)-3-Amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode.
  Biol Chem, 383, 1185-1191.
PDB codes: 1kye 3liw
11170384 D.Kirchhofer, C.Eigenbrot, M.T.Lipari, P.Moran, M.Peek, and R.F.Kelley (2001).
The tissue factor region that interacts with factor Xa in the activation of factor VII.
  Biochemistry, 40, 675-682.  
11371189 F.C.Peterson, N.C.Gordon, and P.G.Gettins (2001).
High-level bacterial expression and 15N-alanine-labeling of bovine trypsin. Application to the study of trypsin-inhibitor complexes and trypsinogen activation by NMR spectroscopy.
  Biochemistry, 40, 6275-6283.  
11371191 J.E.Grundy, N.Lavigne, T.Hirama, C.R.MacKenzie, and E.L.Pryzdial (2001).
Binding of plasminogen and tissue plasminogen activator to plasmin-modulated factor X and factor Xa.
  Biochemistry, 40, 6293-6302.  
11151012 R.Walser, and W.F.van Gunsteren (2001).
Viscosity dependence of protein dynamics.
  Proteins, 42, 414-421.  
10869434 J.L.Harris, B.J.Backes, F.Leonetti, S.Mahrus, J.A.Ellman, and C.S.Craik (2000).
Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries.
  Proc Natl Acad Sci U S A, 97, 7754-7759.  
11027132 M.Adler, D.D.Davey, G.B.Phillips, S.H.Kim, J.Jancarik, G.Rumennik, D.R.Light, and M.Whitlow (2000).
Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa.
  Biochemistry, 39, 12534-12542.
PDB code: 1fjs
10713516 R.Krishnan, I.Mochalkin, R.Arni, and A.Tulinsky (2000).
Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1.
  Acta Crystallogr D Biol Crystallogr, 56, 294-303.
PDB codes: 1c4u 1c4v 1c4y 1d6w 1d9i
11087381 R.M.Camire, P.J.Larson, D.W.Stafford, and K.A.High (2000).
Enhanced gamma-carboxylation of recombinant factor X using a chimeric construct containing the prothrombin propeptide.
  Biochemistry, 39, 14322-14329.  
  10716178 R.St Charles, K.Padmanabhan, R.V.Arni, K.P.Padmanabhan, and A.Tulinsky (2000).
Structure of tick anticoagulant peptide at 1.6 A resolution complexed with bovine pancreatic trypsin inhibitor.
  Protein Sci, 9, 265-272.
PDB code: 1d0d
10839461 S.Sperl, A.Bergner, J.Stürzebecher, V.Magdolen, W.Bode, and L.Moroder (2000).
Urethanyl-3-amidinophenylalanine derivatives as inhibitors of factor Xa. X-ray crystal structure of a trypsin/inhibitor complex and modeling studies.
  Biol Chem, 381, 321-329.  
10801494 V.L.Nienaber, D.Davidson, R.Edalji, V.L.Giranda, V.Klinghofer, J.Henkin, P.Magdalinos, R.Mantei, S.Merrick, J.M.Severin, R.A.Smith, K.Stewart, K.Walter, J.Wang, M.Wendt, M.Weitzberg, X.Zhao, and T.Rockway (2000).
Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite.
  Structure, 8, 553-563.  
10545181 A.Betz, P.W.Wong, and U.Sinha (1999).
Inhibition of factor Xa by a peptidyl-alpha-ketothiazole involves two steps. Evidence for a stabilizing conformational change.
  Biochemistry, 38, 14582-14591.  
10430872 A.C.Pike, A.M.Brzozowski, S.M.Roberts, O.H.Olsen, and E.Persson (1999).
Structure of human factor VIIa and its implications for the triggering of blood coagulation.
  Proc Natl Acad Sci U S A, 96, 8925-8930.
PDB code: 1qfk
10102985 H.Czapinska, and J.Otlewski (1999).
Structural and energetic determinants of the S1-site specificity in serine proteases.
  Eur J Biochem, 260, 571-595.  
10089309 I.Mochalkin, and A.Tulinsky (1999).
Structures of thrombin retro-inhibited with SEL2711 and SEL2770 as they relate to factor Xa binding.
  Acta Crystallogr D Biol Crystallogr, 55, 785-793.
PDB codes: 7kme 8kme
10467148 K.P.Hopfner, A.Lang, A.Karcher, K.Sichler, E.Kopetzki, H.Brandstetter, R.Huber, W.Bode, and R.A.Engh (1999).
Coagulation factor IXa: the relaxed conformation of Tyr99 blocks substrate binding.
  Structure, 7, 989-996.
PDB code: 1rfn
10022353 M.S.Rao, and A.J.Olson (1999).
Modelling of factor Xa-inhibitor complexes: a computational flexible docking approach.
  Proteins, 34, 173-183.  
10417407 M.Whitlow, D.O.Arnaiz, B.O.Buckman, D.D.Davey, B.Griedel, W.J.Guilford, S.K.Koovakkat, A.Liang, R.Mohan, G.B.Phillips, M.Seto, K.J.Shaw, W.Xu, Z.Zhao, D.R.Light, and M.M.Morrissey (1999).
Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin.
  Acta Crystallogr D Biol Crystallogr, 55, 1395-1404.
PDB codes: 1qa0 1qb1 1qb6 1qb9 1qbn 1qbo
10189177 P.E.Sanderson (1999).
Small, noncovalent serine protease inhibitors.
  Med Res Rev, 19, 179-197.  
10498211 S.Y.Tamura, E.A.Goldman, P.W.Bergum, and J.E.Semple (1999).
Novel benzo-fused lactam scaffolds as factor Xa inhibitors.
  Bioorg Med Chem Lett, 9, 2573-2578.  
10440994 Y.Zhou, and M.E.Johnson (1999).
Comparative molecular modeling analysis of-5-amidinoindole and benzamidine binding to thrombin and trypsin: specific H-bond formation contributes to high 5-amidinoindole potency and selectivity for thrombin and factor Xa.
  J Mol Recognit, 12, 235-241.  
9736916 A.S.Ripka, and D.H.Rich (1998).
Peptidomimetic design.
  Curr Opin Chem Biol, 2, 441-452.  
9609717 A.W.Ashton, M.K.Boehm, D.J.Johnson, G.Kemball-Cook, and S.J.Perkins (1998).
The solution structure of human coagulation factor VIIa in its complex with tissue factor is similar to free factor VIIa: a study of a heterodimeric receptor-ligand complex by X-ray and neutron scattering and computational modeling.
  Biochemistry, 37, 8208-8217.  
9517542 F.Fraternali, Q.T.Do, B.T.Doan, R.A.Atkinson, P.Palmas, V.Sklenar, P.Safar, P.Wildgoose, P.Strop, and V.Saudek (1998).
Mapping the active site of factor Xa by selective inhibitors: an NMR and MD study.
  Proteins, 30, 264-274.  
9736918 J.A.Shafer (1998).
Cardiovascular chemotherapy: anticoagulants.
  Curr Opin Chem Biol, 2, 458-465.  
9618463 K.Kamata, H.Kawamoto, T.Honma, T.Iwama, and S.H.Kim (1998).
Structural basis for chemical inhibition of human blood coagulation factor Xa.
  Proc Natl Acad Sci U S A, 95, 6630-6635.
PDB codes: 1xka 1xkb
9707558 K.P.Hopfner, E.Kopetzki, G.B.Kresse, W.Bode, R.Huber, and R.A.Engh (1998).
New enzyme lineages by subdomain shuffling.
  Proc Natl Acad Sci U S A, 95, 9813-9818.
PDB code: 1fxy
9753698 M.A.Parry, U.Jacob, R.Huber, A.Wisner, C.Bon, and W.Bode (1998).
The crystal structure of the novel snake venom plasminogen activator TSV-PA: a prototype structure for snake venom serine proteinases.
  Structure, 6, 1195-1206.
PDB code: 1bqy
9362477 K.P.Hopfner, H.Brandstetter, A.Karcher, E.Kopetzki, R.Huber, R.A.Engh, and W.Bode (1997).
Converting blood coagulation factor IXa into factor Xa: dramatic increase in amidolytic activity identifies important active site determinants.
  EMBO J, 16, 6626-6635.  
9305622 M.Renatus, R.A.Engh, M.T.Stubbs, R.Huber, S.Fischer, U.Kohnert, and W.Bode (1997).
Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA.
  EMBO J, 16, 4797-4805.
PDB code: 1bda
9311976 R.Lapatto, U.Krengel, H.A.Schreuder, A.Arkema, B.de Boer, K.H.Kalk, W.G.Hol, P.D.Grootenhuis, J.W.Mulders, R.Dijkema, H.J.Theunissen, and B.W.Dijkstra (1997).
X-ray structure of antistasin at 1.9 A resolution and its modelled complex with blood coagulation factor Xa.
  EMBO J, 16, 5151-5161.
PDB code: 1skz
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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