PDBsum entry 2evc

Hydrolase

PDB id: 2evc

Contents

Protein chain

259 a.a. *

Ligands

FC3

Metals

_MN ×2

_NA

Waters ×171

* Residue conservation analysis

PDB id:

2evc

Name:

Hydrolase

Title:

Crystal structure of e. Coli. Methionine amino peptidase in complex with 5-(2-(trifluoromethyl)phenyl)furan-2-carboxylic acid

Structure:

Methionine aminopeptidase. Chain: a. Synonym: map, peptidase m. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.60Å R-factor: 0.210 R-free: 0.229

Authors:

W.-J.Huang

Key ref:

S.X.Xie et al. (2006). Structural analysis of metalloform-selective inhibition of methionine aminopeptidase. Acta Crystallogr D Biol Crystallogr, 62, 425-432. PubMed id: 16552144 DOI: 10.1107/S0907444906003878

Date:

31-Oct-05 Release date: 28-Mar-06

Protein chain

P0AE18  (MAP1_ECOLI) -  Methionine aminopeptidase from Escherichia coli (strain K12)

Seq: 264 a.a.

Struc: 259 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.11.18 - methionyl aminopeptidase.
• Reaction: Release of N-terminal amino acids, preferentially methionine, from peptides and arylamides.
• Cofactor: Cobalt cation

DOI no: 10.1107/S0907444906003878

Acta Crystallogr D Biol Crystallogr 62:425-432 (2006)

PubMed id: 16552144

Structural analysis of metalloform-selective inhibition of methionine aminopeptidase.

S.X.Xie, W.J.Huang, Z.Q.Ma, M.Huang, R.P.Hanzlik, Q.Z.Ye.

ABSTRACT

One of the challenges in the development of methionine aminopeptidase (MetAP) inhibitors as antibacterial and anticancer agents is to define the metal ion actually used by MetAP in vivo and to discover MetAP inhibitors that can inhibit the metalloform that is relevant in vivo. Two distinct classes of novel nonpeptidic MetAP inhibitors that are not only potent but also highly selective for either the Mn(II) or Co(II) form have been identified. Three crystal structures of Escherichia coli MetAP complexed with the metalloform-selective inhibitors 5-(2,5-dichlorophenyl)furan-2-carboxylic acid (2), 5-[2-(trifluoromethyl)phenyl]furan-2-carboxylic acid (3) and N-cyclopentyl-N-(thiazol-2-yl)oxalamide (4) have been solved and analysis of these structures has revealed the structural basis for their metalloform-selective inhibition. The Mn(II)-form selective inhibitors (2) and (3) both use their carboxylate group to coordinate with the two Mn(II) ions at the dinuclear metal site and both adopt a non-coplanar conformation for the two aromatic rings. The unique coordination geometry of these inhibitors may determine their Mn(II)-form selectivity. In contrast, the Co(II)-form selective inhibitor (4) recruits an unexpected third metal ion, forming a trimetallic enzyme-metal-inhibitor complex. Thus, an important factor in the selectivity of (4) for the Co(II) form may be a consequence of a greater preference for a softer N,O-donor ligand for the softer Co(II).

Selected figure(s)

Figure 1.
Figure 1 Structures of the inhibitors used for crystallization and structure solution. Inhibitors (1), (2) and (3) are MnII-form selective, while inhibitor (4) is CoII-form selective.

Figure 4.
Figure 4 Stereoviews of inhibitors (2), (3) and (4) at the enzyme active site. Unbiased F[obs] - F[calc] electron-density maps showing the inhibitors and metal ions are contoured at 3 . (a) The MnII-form selective inhibitor (2) with the MnII-form enzyme. (b) The MnII-form selective inhibitor (3) with the MnII-form enzyme. (c) The CoII-form selective inhibitor (4) with the CoII-form enzyme. For clarity, only the five conserved residues forming the common dinuclear metal site (Asp97, Asp108, His171, Glu204 and Glu235) plus His79 and His178 are shown. Protein residues are colored grey for carbon, red for oxygen and blue for nitrogen. Inhibitors are colored the same way, except that carbons are yellow, sulfurs orange, chlorines green and fluorines cyan. MnII ions are shown as green spheres, while CoII ions are shown as magenta spheres. Water molecules are shown as smaller red spheres. Hydrogen bonds and metal interactions are shown as black dashed lines.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2006, 62, 425-432) copyright 2006.

Figures were selected by an automated process.