PDBsum entry 3cs7

Hydrolase

PDB id: 3cs7

Contents

Protein chains

234 a.a. *

52 a.a. *

Ligands

LG0

Metals

_CA

Waters ×119

* Residue conservation analysis

PDB id:

3cs7

Name:

Hydrolase

Title:

Factor xa in complex with the inhibitor 1-(4-methoxyphenyl)-6-(4-(1- (pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)-3-(trifluoromethyl)-5,6- dihydro-1h-pyrazolo[3,4-c]pyridin-7(4h)-one

Structure:

Coagulation factor x. Chain: a. Fragment: coagulation factor x, heavy chain. Synonym: stuart factor, stuart-prower factor, factor x light chain, factor x heavy chain, activated factor xa heavy chain. Coagulation factor x. Chain: l. Fragment: coagulation factor x, light chain. Synonym: stuart factor, stuart-prower factor, factor x light chain,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Other_details: proteolytic cleavage product. Other_details: proteolytic cleavage product

Resolution:

2.20Å R-factor: 0.225 R-free: 0.274

Authors:

R.S.Alexander

Key ref:

J.X.Qiao et al. (2008). Achieving structural diversity using the perpendicular conformation of alpha-substituted phenylcyclopropanes to mimic the bioactive conformation of ortho-substituted biphenyl P4 moieties: discovery of novel, highly potent inhibitors of Factor Xa. Bioorg Med Chem Lett, 18, 4118-4123. PubMed id: 18550370 DOI: 10.1016/j.bmcl.2008.05.095

Date:

09-Apr-08 Release date: 08-Jul-08

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 234 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, L: E.C.3.4.21.6 - coagulation factor Xa.
• Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

DOI no: 10.1016/j.bmcl.2008.05.095

Bioorg Med Chem Lett 18:4118-4123 (2008)

PubMed id: 18550370

Achieving structural diversity using the perpendicular conformation of alpha-substituted phenylcyclopropanes to mimic the bioactive conformation of ortho-substituted biphenyl P4 moieties: discovery of novel, highly potent inhibitors of Factor Xa.

J.X.Qiao, D.L.Cheney, R.S.Alexander, A.M.Smallwood, S.R.King, K.He, A.R.Rendina, J.M.Luettgen, R.M.Knabb, R.R.Wexler, P.Y.Lam.

ABSTRACT

Ortho-substituted biphenyl moieties are widely used in drug design. We herein report a successful use of the perpendicular conformation of the alpha-substituted phenylcyclopropyl groups to mimic the aplanar, biologically active conformation of the ortho-substituted biphenyl moieties to achieve structural diversity. This is exemplified by the design and synthesis of a series of highly potent pyrazole bicyclic-based Factor Xa (FXa) inhibitors bearing alpha-substituted phenylcyclopropyl P4 moieties. The designed perpendicular conformation was confirmed by the X-ray structure of FXa-bound compound 2r. The potential structural basis for the high FXa potency in the phenylcyclopropyl P4 analogs and their improved FXa inhibitory activities compared with the biphenyl P4 counterparts are discussed.