PDBsum entry 1nt1

Blood clotting/hydrolase inhibitor

PDB id: 1nt1

Contents

Protein chains

276 a.a. *

11 a.a. *

Ligands

T76

Waters ×143

* Residue conservation analysis

PDB id:

1nt1

Name:

Blood clotting/hydrolase inhibitor

Title:

Thrombin in complex with selective macrocyclic inhibitor

Structure:

Thrombin. Chain: a. Synonym: coagulation factor ii. Hirudin. Chain: h. Engineered: yes. Other_details: 10 aa hirudin analogue

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: plasma from blood. Synthetic: yes

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.190

Authors:

P.G.Nantermet,J.C.Barrow,C.L.Newton,J.M.Pellicore,M.Young,S.D.Lewis, B.J.Lucas,J.A.Krueger,D.R.Mcmasters,Y.Yan,L.C.Kuo,J.P.Vacca, H.G.Selnick

Key ref:

P.G.Nantermet et al. (2003). Design and synthesis of potent and selective macrocyclic thrombin inhibitors. Bioorg Med Chem Lett, 13, 2781-2784. PubMed id: 12873514 DOI: 10.1016/S0960-894X(03)00506-7

Date:

28-Jan-03 Release date: 02-Sep-03

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 3 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/S0960-894X(03)00506-7

Bioorg Med Chem Lett 13:2781-2784 (2003)

PubMed id: 12873514

Design and synthesis of potent and selective macrocyclic thrombin inhibitors.

P.G.Nantermet, J.C.Barrow, C.L.Newton, J.M.Pellicore, M.Young, S.D.Lewis, B.J.Lucas, J.A.Krueger, D.R.McMasters, Y.Yan, L.C.Kuo, J.P.Vacca, H.G.Selnick.

ABSTRACT

A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity.