Mapping the conformational space accessible to catechol-O-methyltransferase

Ehler, A.; Benz, J.; Schlatter, D.; Rudolph, M.G.

doi:10.1107/S1399004714012917

Figure 7
Binding of the inhibitor 4-[3-(3-aminomethylphenyl)-ureido]-benzamidine to the surface of humanized rat apo COMT. (a) Superposition of the apo COMT structures (5) and (6) with the complex structure (12) (green). The orientation is the same as in Fig. 5

and shows two notable side-chain differences for His185 and Arg189 in the complex structure. (b) The 2mF_o − DF_c electron-density map for the ligand is contoured at 1.5 r.m.s.d. (blue). The mF_o − DF_c OMIT map is contoured at 2.5 r.m.s.d. (red). From the densities it is apparent that the benzamidine moiety is the best ordered part of the ligand. The positively charged head group forms two hydrogen bonds to Asp188. Another hydrogen bond is formed between the carbonyl group of the urea moiety and Asn135. The two aromatic parts of the inhibitor are in van der Waals contact with Trp186, Ile134 and Pro136. A close contact between the side chain of Asn135 and the inhibitor may explain the relatively low affinity of the compound. A water-filled cavity (red spheres) is cordoned off by the inhibitor, leaving options for inhibitor improvement by water displacement. Although the structure is with humanized rat COMT, all residues that contact the inhibitor are conserved in human COMT and the binding mode will thus be the same for both forms. Hydrogen bonds, van der Waals interactions and clashes are shown as black, magenta and red dashed lines, respectively.

BIOLOGICAL
CRYSTALLOGRAPHY

ISSN: 1399-0047

Volume 70| Part 8| July 2014| Pages 2163-2174

doi:10.1107/S1399004714012917

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