PDBsum entry 1zhp

Hydrolase, blood clotting

PDB id: 1zhp

Contents

Protein chain

237 a.a. *

Ligands

BEN

GSH

Waters ×53

* Residue conservation analysis

PDB id:

1zhp

Name:

Hydrolase, blood clotting

Title:

Crystal structure of the catalytic domain of coagulation factor xi in complex with benzamidine (s434a-t475a-k505 mutant)

Structure:

Coagulation factor xi. Chain: a. Fragment: catalytic domain. Synonym: plasma thromboplastin antecedent. Pta. Fxi. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: pichia pastoris. Expression_system_taxid: 4922. Expression_system_cell_line: x-33

Resolution:

2.70Å R-factor: 0.208 R-free: 0.257

Authors:

L.Jin,P.Pandey,R.E.Babine,D.T.Weaver,S.S.Abdel-Meguid,J.E.Strickler

Key ref:

L.Jin et al. (2005). Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors. Acta Crystallogr D Biol Crystallogr, 61, 1418-1425. PubMed id: 16204896 DOI: 10.1107/S0907444905024340

Date:

26-Apr-05 Release date: 20-Sep-05

Protein chain

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 237 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.27 - coagulation factor XIa.
• Reaction: Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.

DOI no: 10.1107/S0907444905024340

Acta Crystallogr D Biol Crystallogr 61:1418-1425 (2005)

PubMed id: 16204896

Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors.

L.Jin, P.Pandey, R.E.Babine, D.T.Weaver, S.S.Abdel-Meguid, J.E.Strickler.

ABSTRACT

Activated factor XI (FXIa) is a key enzyme in the amplification phase of the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser bleeding liabilities and provide a safe alternative for antithrombosis therapy to available drugs on the market. In a previous report, the crystal structures of the catalytic domain of FXIa (rhFXI(370-607)) in complex with various ecotin mutants have been described. However, ecotin forms a matrix-like interaction with rhFXI(370-607) and is impossible to displace with small-molecule inhibitors; ecotin crystals are therefore not suitable for iterative structure-based ligand design. In addition, rhFXI(370-607) did not crystallize in the presence of small-molecule ligands. In order to obtain the crystal structure of rhFXI(370-607) with a weak small-molecule ligand, namely benzamidine, several rounds of surface-residue mutation were implemented to promote crystal formation of rhFXI(370-607). A quadruple mutant of rhFXI(370-607) (rhFXI(370-607)-S434A,T475A,C482S,K437A) readily crystallized in the presence of benzamidine. The benzamidine in the preformed crystals was easily exchanged with other FXIa small-molecule inhibitors. These crystals have facilitated the structure-based design of small-molecule FXIa inhibitors.

Selected figure(s)

Figure 4.
Figure 4 View of the benzamidine-binding site in the rhFXI[370-607]-S434A,T475A,C482S,K437A-benzamidine structure. Benzamidine, a sulfate molecule in the oxyanion hole and a water molecule are shown as a ball-and-stick representation. The residues around benzamidine are shown as a stick representation. The hydrogen bonds between benzamidine and the protein are shown by black lines with bond distances labeled in Å.

Figure 5.
Figure 5 Examples of different classes of ligand soaked into rhFXI[370-607]-S434A,T475A,C482S,K437A-benzamidine crystals. The active site of rhFXI[370-607]-S434A,T475A,C482S,K437A is presented in a stick representation, with the catalytic triad (Ser195, His57 and Asp102) and Asp189 labeled. The ligands are in a ball-and-stick representation and their chemical structures are listed under each picture. (a) A peptide-mimetic ligand covalently connects to Ser195. (b) A naphthamidine ligand replaces benzamidine at the active site. (c) A non-basic small compound binds in the S[1] pocket.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2005, 61, 1418-1425) copyright 2005.

Figures were selected by the author.