PDBsum entry 2wyg

Blood clotting

PDB id: 2wyg

Contents

Protein chains

228 a.a. *

52 a.a. *

Ligands

461

Waters ×210

* Residue conservation analysis

PDB id:

2wyg

Name:

Blood clotting

Title:

Structure and property based design of factor xa inhibitors: pyrrolidin-2-ones with monoaryl p4 motifs

Structure:

Activated factor xa heavy chain. Chain: a. Fragment: activated desgla, residues 235-488. Other_details: disulphide linked to other chain. Factor x light chain. Chain: b. Fragment: activated desgla, residues 46-179. Other_details: disulphide linked to other chain

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Other_details: purchased from enzyme research labs, isolated from human blood. Human blood

Resolution:

1.88Å R-factor: 0.198 R-free: 0.234

Authors:

S.Kleanthous,A.D.Borthwick,D.Brown,C.L.Burns-Kurtis,M.Campbell, L.Chaudry,C.Chan,M.Clarte,M.A.Convery,J.D.Harling,E.Hortense, W.R.Irving,S.Irvine,A.J.Pateman,A.Patikis,I.L.Pinto,D.R.Pollard, T.J.Roethka,S.Senger,G.P.Shah,G.J.Stelman,J.R.Toomey,N.S.Watson, C.Whittaker,P.Zhou,R.J.Young

Key ref:

S.Kleanthous et al. (2010). Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs. Bioorg Med Chem Lett, 20, 618-622. PubMed id: 20006499

Date:

16-Nov-09 Release date: 01-Dec-10

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 228 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 52 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.21.6 - coagulation factor Xa.
• Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

Bioorg Med Chem Lett 20:618-622 (2010)

PubMed id: 20006499

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

S.Kleanthous, A.D.Borthwick, D.Brown, C.L.Burns-Kurtis, M.Campbell, L.Chaudry, C.Chan, M.O.Clarte, M.A.Convery, J.D.Harling, E.Hortense, W.R.Irving, S.Irvine, A.J.Pateman, A.N.Patikis, I.L.Pinto, D.R.Pollard, T.J.Roethka, S.Senger, G.P.Shah, G.J.Stelman, J.R.Toomey, N.S.Watson, R.I.West, C.Whittaker, P.Zhou, R.J.Young.

ABSTRACT

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.