Homology-based molecular modelling of PLP-dependent histidine decarboxylase from Mmorganella morganii.
The 3-D structural information is a prerequisite for a rational ligand design. In the absence of experimental data, model building on the basis of a known 3-D structure of a homologous protein is at present the only reliable method to obtain structural information. A homology model building study of the pyridoxal 5'-phosphate (PLP)-dependent histidine decarboxylase from Morganella morganii (HDC-MM) has been carried out based on the crystal structure of the aspartate aminotransferase from Escherichia coli (AAT-EC). The primary sequences of AAT-EC and HDC-MM were aligned by automated alignment procedure. A 3-D model of HDC-MM was constructed by copying the coordinates of the residues from the crystal structure of AAT-EC into the corresponding residues in HDC-MM. After energy-minimization of the resulting 3-D model of HDC-MM, possible active site residues were identified by fitting the substrate (l-histidine) into the proposed active-site. In our model, several residues, which have an important role in the AAT-EC active-site, are located in positions spatially identical to those in AAT-EC structure. The back-bone of the modelled active site pocket is constructed by residues; Gly-92, Gly-93, Thr-93, Ser-115, Asp-200, Ala-202, Ser-229 and Lys-232 together with residues Asn-8, His-119, Thr-171, His-198, Leu-203, His-231, Ser-236 and Ile-238. In the ligand binding site, it appears that the HDC-MM model will position l-histidine (substrate) in the area consisting of the residues; Glu-29, Ser-30, Leu-38, His-231 and Lys-232. The nitrogen atom of the imidazole ring (N2) of the substrate is predicted to interact with the carboxylate group of Ser-30. The alpha-carboxylate of histidine points toward the Lys-232 to have electrostatic interaction with its side chain nitrogen atom (N(Z)). In conclusion, this combination of sequence and 3-D structural homology between AAT-EC and HDC-MM model could provide insight in assigning the probable active site residues.
Tahanejad
F S
FS
Department of Pharmacology, Baghiyatollah University of Medical Sciences, P.O. Box: 19585-698, Tehran, Iran.
Naderi-Manesh
H
H
Habibinejad
B
B
Mahmoudian
M
M
D000595:Amino Acid Sequence; D001219:Aspartate Aminotransferases / Q000737:chemistry; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D017124:Conserved Sequence; D004926:Escherichia coli / Q000201:enzymology; D006640:Histidine Decarboxylase / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020613:Morganella morganii / Q000201:enzymology*; D011422:Propionates / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011732:Pyridoxal Phosphate / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012984:Software
C412575:2-amino-2-methyl-3-(2-benzimidazolyl)propionic acid; D001562:Benzimidazoles; D011422:Propionates; D011732:Pyridoxal Phosphate; D001219:Aspartate Aminotransferases; D006640:Histidine Decarboxylase