PDBsum entry 1z71

Hydrolase/hydrolase inhibitor

PDB id: 1z71

Contents

Protein chains

276 a.a. *

11 a.a. *

Ligands

L17

Waters ×194

* Residue conservation analysis

PDB id:

1z71

Name:

Hydrolase/hydrolase inhibitor

Title:

Thrombin and p2 pyridine n-oxide inhibitor complex structure

Structure:

Thrombin. Chain: a. Fragment: alpha-thrombin. Synonym: coagulation factor ii. Hirudin iiib'. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes. Hirudo medicinalis. Organism_taxid: 6421. Other_details: occurs naturally in medicinal leech hirudo medicinalis

Biol. unit:

Dimer (from PQS)

Resolution:

1.80Å R-factor: 0.223 R-free: 0.254

Authors:

P.G.Nantermet,C.S.Burgey,K.A.Robinson,J.M.Pellicore,C.L.Newton, J.Z.Deng,T.A.Lyle,H.G.Selnick,S.D.Lewis,B.J.Lucas,J.A.Krueger, C.Miller-Stein,R.B.White,B.Wong,D.R.Mcmasters,A.A.Wallace,J.J.Lynch Jr.,Y.Yan,Z.Chen,L.Kuo,S.J.Gardell,J.A.Shafer,J.P.Vacca

Key ref:

P.G.Nantermet et al. (2005). P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold. Bioorg Med Chem Lett, 15, 2771-2775. PubMed id: 15911253 DOI: 10.1016/j.bmcl.2005.03.110

Date:

23-Mar-05 Release date: 17-May-05

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 276 a.a.

Protein chain

P28504  (HIR2_HIRME) -  Hirudin-2 from Hirudo medicinalis

Seq: 65 a.a.

Struc: 11 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

DOI no: 10.1016/j.bmcl.2005.03.110

Bioorg Med Chem Lett 15:2771-2775 (2005)

PubMed id: 15911253

P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold.

P.G.Nantermet, C.S.Burgey, K.A.Robinson, J.M.Pellicore, C.L.Newton, J.Z.Deng, H.G.Selnick, S.D.Lewis, B.J.Lucas, J.A.Krueger, C.Miller-Stein, R.B.White, B.Wong, D.R.McMasters, A.A.Wallace, J.J.Lynch, Y.Yan, Z.Chen, L.Kuo, S.J.Gardell, J.A.Shafer, J.P.Vacca, T.A.Lyle.

ABSTRACT

In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).