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Hydrolase PDB-id
1nfw
Biological unit* = asymmetric unit,
as shown
(*as deduced by PQS)
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Description
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PROCHECK
Protein chains
234 a.a. *
51 a.a. *
Ligands
RRR
Metal ions
_CA
Waters ×170

* Residue conservation analysis
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PDB id: 1nfw
Name: Hydrolase
Title: Crystal structure of human coagulation factor xa complexed with rpr209685

Structure:
Coagulation factor xa, heavy chain. Chain: a. Synonym: activated factor xa, heavy chain. Coagulation factor xa, light chain. Chain: b. Synonym: factor x light chain. Ec: 3.4.21.6

Source:
Homo sapiens. Human. Organism_taxid: 9606. Other_details: blood. Other_details: blood

Biological unit:
Dimer (from PQS)

UniProt:
Chain A: P00742 (FA10_HUMAN)
Pfam   ArchSchema ?
Seq:
Struc:
Seq: 488 a.a.
Struc: 234 a.a.

Chain B: P00742 (FA10_HUMAN)
Pfam   ArchSchema ?
Seq:
Struc:
Seq: 488 a.a.
Struc: 51 a.a.
Key:    PfamA domain
 Secondary structure  CATH domain

Enzyme class:
Chains A, B: E.C.3.4.21.6   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:
Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

Resolution:
2.10Å

R-factor:
0.200

Authors:
S.Maignan,J.P.Guilloteau

Key ref:
S.Maignan et al. (2003). Molecular structures of human factor Xa complexed with ketopiperazine inhibitors: preference for a neutral group in the S1 pocket.. J Med Chem, 46, 685-690. [PubMed id: 12593649] [DOI: 10.1021/jm0203837]

Date:
16-Dec-02

Release date:
25-Feb-03

Related entries:
1ezq
the same protein complexed with rpr128515
1for
the same protein complexed with rpr208815
1fos
the same protein complexed with rpr208707
1nfu
1nfx
1nfy
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    Key reference    
 
 
DOI no: 10.1021/jm0203837 J Med Chem 46:685-690 (2003)
PubMed id: 12593649  
 
 
Molecular structures of human factor Xa complexed with ketopiperazine inhibitors: preference for a neutral group in the S1 pocket.
S.Maignan, J.P.Guilloteau, Y.M.Choi-Sledeski, M.R.Becker, W.R.Ewing, H.W.Pauls, A.P.Spada, V.Mikol.
 
  ABSTRACT  
 
The structures of the noncovalent complex of human factor Xa (fXa) with four non-peptide inhibitors containing a central sulfonylpiperazinone scaffold have been determined to about 2.1 A resolution. Highly potent fXa inhibitors containing both neutral groups such as chlorobenzothiophene or chlorothiophene and basic groups such as benzamidine were shown to interact in the S1 pocket through the neutral group whereas the S4 pocket is occupied by the basic moiety. The scaffold comprising the sulfonyl keto piperazine moiety might play a pivotal role in the orientation of substituents, since there is a strong hydrogen bond between Gly219 of fXa and the carbonyl oxygen of the piperazine. This unique "reverse" binding mode is heretofore unreported in fXa and shows that electrostatic interactions in the S1 subsite are not an absolute requirement to maintain high affinity. Selectivity against other serine proteases can be readily explained in light of these structural results. It has opened up new prospects for designing fXa inhibitors with increased oral bioavailability.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19671127 F.Quintus, O.Sperandio, J.Grynberg, M.Petitjean, and P.Tuffery (2009).
Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity.
  BMC Bioinformatics, 10, 245.  
19641793 M.Limbach, A.V.Lygin, V.S.Korotkov, M.Es-Sayed, and A.de Meijere (2009).
Facile synthesis of structurally diverse 5-oxopiperazine-2-carboxylates as dipeptide mimics and templates.
  Org Biomol Chem, 7, 3338-3342.  
19089820 C.Krishnasamy, A.Raghuraman, L.B.Kier, and U.R.Desai (2008).
Application of molecular connectivity and electro-topological indices in quantitative structure-activity analysis of pyrazole derivatives as inhibitors of factor xa and thrombin.
  Chem Biodivers, 5, 2609-2620.  
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.  
18434503 Y.N.Imai, Y.Inoue, I.Nakanishi, and K.Kitaura (2008).
Cl-pi interactions in protein-ligand complexes.
  Protein Sci, 17, 1129-1137.  
17581239 C.A.Van Huis, C.F.Bigge, A.Casimiro-Garcia, W.L.Cody, D.A.Dudley, K.J.Filipski, R.J.Heemstra, J.T.Kohrt, L.S.Narasimhan, R.P.Schaum, E.Zhang, J.W.Bryant, S.Haarer, N.Janiczek, R.J.Leadley, T.McClanahan, J.Thomas Peterson, K.M.Welch, and J.J.Edmunds (2007).
Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.
  Chem Biol Drug Des, 69, 444-450.
PDB code: 2pr3
17683371 J.T.Kohrt, C.F.Bigge, J.W.Bryant, A.Casimiro-Garcia, L.Chi, W.L.Cody, T.Dahring, D.A.Dudley, K.J.Filipski, S.Haarer, R.Heemstra, N.Janiczek, L.Narasimhan, T.McClanahan, J.T.Peterson, V.Sahasrabudhe, R.Schaum, C.A.Van Huis, K.M.Welch, E.Zhang, R.J.Leadley, and J.J.Edmunds (2007).
The discovery of (2R,4R)-N-(4-chlorophenyl)-N- (2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor.
  Chem Biol Drug Des, 70, 100-112.
PDB code: 2phb
16511824 R.Fasan, R.L.Dias, K.Moehle, O.Zerbe, D.Obrecht, P.R.Mittl, M.G.Grütter, and J.A.Robinson (2006).
Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction.
  Chembiochem, 7, 515-526.
PDB code: 2axi
15952226 K.Schärer, M.Morgenthaler, R.Paulini, U.Obst-Sander, D.W.Banner, D.Schlatter, J.Benz, M.Stihle, and F.Diederich (2005).
Quantification of cation-pi interactions in protein-ligand complexes: crystal-structure analysis of Factor Xa bound to a quaternary ammonium ion ligand.
  Angew Chem Int Ed Engl, 44, 4400-4404.
PDB code: 2bok
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.