PDBsum entry 3da9

Hydrolase

PDB id: 3da9

Contents

Protein chains

27 a.a. *

251 a.a. *

Ligands

ASP-PHE-GLU-GLU-ILE-PRO-GLY-GLU-PTR

44U

Metals

_NA

Waters ×277

* Residue conservation analysis

PDB id:

3da9

Name:

Hydrolase

Title:

Crystal structure of thrombin in complex with inhibitor

Structure:

Thrombin light chain. Chain: a. Fragment: unp residues 328-363. Synonym: coagulation factor ii, activation peptide fragment 1, activation peptide fragment 2, thrombin light chain. Thrombin heavy chain. Chain: b. Fragment: unp residues 364-622. Synonym: coagulation factor ii, activation peptide fragment 1,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes

Resolution:

1.80Å R-factor: 0.184 R-free: 0.215

Authors:

Y.Xue,S.K.Hansson

Key ref:

M.Nilsson et al. (2009). Compounds binding to the S2-S3 pockets of thrombin. J Med Chem, 52, 2708-2715. PubMed id: 19371038

Date:

29-May-08 Release date: 19-May-09

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 27 a.a.

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 251 a.a.

Enzyme reactions

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

J Med Chem 52:2708-2715 (2009)

PubMed id: 19371038

Compounds binding to the S2-S3 pockets of thrombin.

M.Nilsson, M.Hämäläinen, M.Ivarsson, J.Gottfries, Y.Xue, S.Hansson, R.Isaksson, T.Fex.

ABSTRACT

A set of compounds designed to bind to the S2-S3 pockets of thrombin was prepared. These compounds included examples with no interactions in the S1 pocket. Proline, a common P2 in many thrombin inhibitors, was combined with known P3 residues and P1 substituents of varying size and lipophilicity. Binding constants were determined using surface plasmon resonance (SPR) biosensor technology and were found to be in good agreement with results from an enzyme assay. A dramatic increase in affinity (100-1000 times) was seen for compounds incorporating an amino group capable of forming a hydrogen bond with gly216 in the protein backbone. The ligand efficiency was increased by including substituents that form stronger hydrophobic interactions with the P1 pocket. The binding mode was confirmed by X-ray analysis, which revealed the anticipated binding motif that included hydrogen bonds as well as a tightly bound water molecule. A QSAR model indicated that hydrogen bonding and lipophilicity were important for the prediction of binding constants. The results described here may have implications for how directed compound libraries for shallow protein pockets, like S2 and S3 in serine proteases, can be designed.