PDBsum entry 1t4u

Hydrolase/hydrolase inhibitor

PDB id

1t4u

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Contents

			Protein chains

					26 a.a.


					249 a.a. *


					11 a.a. *

			Ligands

					81A

			Waters ×369

* Residue conservation analysis

PDB id:

1t4u

Links
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Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure analysis of a novel oxyguanidine bound to thrombin

Structure:

Prothrombin. Chain: l. Fragment: sequence database residues 334-359. Synonym: coagulation factor ii. Engineered: yes. Prothrombin. Chain: h. Fragment: sequence database residues 364-622. Synonym: coagulation factor ii.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f2. Hirudo medicinalis. Medicinal leech. Organism_taxid: 6421

Biol. unit:

Trimer (from PQS)

Resolution:

2.00Å

R-factor:

0.211

Authors:

J.Spurlino

Key ref:

T.Lu et al. (2004). Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis. Bioorg Med Chem Lett, 14, 3727-3731. PubMed id: 15203151 DOI: 10.1016/j.bmcl.2004.05.002

Date:

30-Apr-04

Release date:

22-Mar-05

PROCHECK

	Headers

	References

Protein chain

P00734 (THRB_HUMAN) - Prothrombin from Homo sapiens

Seq: Struc:

Seq: Struc:					622 a.a. 26 a.a.

Protein chain

P00734 (THRB_HUMAN) - Prothrombin from Homo sapiens

Seq: Struc:

Seq: Struc:					622 a.a. 249 a.a.

Protein chain

P28504 (HIR2_HIRME) - Hirudin-2 from Hirudo medicinalis

Seq: Struc:					65 a.a. 11 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)



		Enzyme reactions

Enzyme class:

Chains L, H: E.C.3.4.21.5 - thrombin.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

DOI no: 10.1016/j.bmcl.2004.05.002	Bioorg Med Chem Lett 14:3727-3731 (2004)
PubMed id: 15203151

Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis.
T.Lu, T.Markotan, F.Coppo, B.Tomczuk, C.Crysler, S.Eisennagel, J.Spurlino, L.Gremminger, R.M.Soll, E.C.Giardino, R.Bone.

ABSTRACT

Through structure-based drug design and parallel synthesis, we have discovered a novel series of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines as guanidine bioisosteres. These compounds have been found to be highly potent, highly selective, and orally bioavailable.

Literature references that cite this PDB file's key reference

PubMed id

Reference

16923023

B.E.Maryanoff, D.F.McComsey, M.J.Costanzo, S.C.Yabut, T.Lu, M.R.Player, E.C.Giardino, and B.P.Damiano (2006).
Exploration of potential prodrugs of RWJ-445167, an oxyguanidine-based dual inhibitor of thrombin and factor Xa.

Chem Biol Drug Des, 68, 29-36.

16047049

R.G.Berlinck, and M.H.Kossuga (2005).
Natural guanidine derivatives.

Nat Prod Rep, 22, 516-550.

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.