TOM: a FRODO subpackage for protein-ligand fitting with interactive energy minimization

Cambillau, Christian; Horjales, E.

doi:10.1016/0263-7855(87)80024-3

Cited by 156 publications

(90 citation statements)

References 20 publications

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“…When refinement proceeded to the point where the use of multiple conformations and anisotropic thermal factors was necessary and appropriate, SHELXL (32) was used. TOM was used for model building for both structures (33). To accommodate model building of the high-resolution structure with multiple conformations and anisotropic thermal factors, XtalView (34) was used.…”

Section: Bacterial Expression and Proteinmentioning

confidence: 99%

Comparison of the Heme-free and -bound Crystal Structures of Human Heme Oxygenase-1

Lad

Schüller

Shimizu

et al. 2003

Journal of Biological Chemistry

113

205

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Heme oxygenase (HO) catalyzes the degradation of heme to biliverdin. The crystal structure of human HO-1 in complex with heme reveals a novel helical structure with conserved glycines in the distal helix, providing flexibility to accommodate substrate binding and product release (Schuller, D. J., Wilks, A., Ortiz de Montellano, P. R., and Poulos, T. L. (1999) Nat. Struct. Biol. 6, 860 -867). To structurally understand the HO catalytic pathway in more detail, we have determined the crystal structure of human apo-HO-1 at 2.1 Å and a higher resolution structure of human HO-1 in complex with heme at 1.5 Å. Although the 1.5-Å heme⅐HO-1 model confirms our initial analysis based on the 2.08-Å model, the higher resolution structure has revealed important new details such as a solvent H-bonded network in the active site that may be important for catalysis. Because of the absence of the heme, the distal and proximal helices that bracket the heme plane in the holo structure move farther apart in the apo structure, thus increasing the size of the active-site pocket. Nevertheless, the relative positioning and conformation of critical catalytic residues remain unchanged in the apo structure compared with the holo structure, but an important solvent H-bonded network is missing in the apoenzyme. It thus appears that the binding of heme and a tightening of the structure around the heme stabilize the solvent H-bonded network required for proper catalysis. Heme oxygenase (HO)1 catalyzes the oxidation of heme to biliverdin and is the key reaction in the recycling of porphyrin and iron in mammals. Biliverdin is reduced by biliverdin reductase to bilirubin, which is then conjugated with glucuronic acid and excreted (1, 2). Excretion of bilirubin is often deficient in newborn children, giving rise to neonatal jaundice and the potential for neurological damage (3). CO, the other product of the HO reaction, has been suggested to serve as a signaling molecule through the guanylate cyclase system in a manner similar to nitric oxide, although this remains a controversial topic (4, 5). Finally, the iron released by HO is normally recycled and represents the major source of this metal in heme homeostasis, whereas increased iron release due to elevated HO activity can trigger enhanced lipid and protein peroxidation (6, 7). There are two HO isoforms, denoted HO-1 and HO-2 (8 -10). A third isoform discovered in rats has been described (11), although the expressed protein is not an active HO, and therefore, its significance is currently unclear.Mammalian HO-1 is a membrane-bound protein.The expression of truncated, water-soluble, fully active forms of human (12) and rat (13) HO-1 missing the C-terminal 23-26 amino acid residues has facilitated major advances in structure/function studies of HO, especially mechanistic studies. The mechanism of HO resembles that of cytochrome P450 in its ability to oxidize unactivated C-H bonds (14). However, in contrast to cytochrome P450 and heme peroxidases, the action of HO does not proceed through a ferryl in...

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Section: Bacterial Expression and Proteinmentioning

confidence: 99%

Comparison of the Heme-free and -bound Crystal Structures of Human Heme Oxygenase-1

Lad

Schüller

Shimizu

et al. 2003

Journal of Biological Chemistry

113

205

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“…The model for the free enzyme at pH 6.0 also represented the initial conformation of glucoamylase-11(471) in the inhibitor complex. A Silicon Graphics 4D25 and the program TOM [15] were used for model building. Initially a single o-gluco-dihydroacarbose molecule in its a-conformation was built into the strongest electron density and refined by restrained least squares [16].…”

Section: B Staffer Et Al Ifebs Letters 358 (1995) 5741mentioning

confidence: 99%

Refined structure for the complex of d‐gluco‐dihydroacarbose with glucoamylase from Aspergillus awamori var. X100 to 2.2 Å resolution: dual conformations for extended inhibitors bound to the active site of glucoamylase

et al. 1995

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The crystal structure at pH 4 of the complex of glucoamylase 11(471) from Aspergiflus awamori var. Xl00 with the pseudotetrasaccharide u-g&o-dihydroaca$mse has been refined to an R-factor of 0.125 against data to 2.2 A resolution. The first two residues of the inhibitor bind at a position nearly identical to those of the closely related inhibitor acarbose in its complex with glucoamylase at pH 6. However, the electron density bifurcates beyond the second residue of the o-gkodihydroacarbose molecule, placing the third and fourth residues together at two positions in the active site. The position of relatively low density (estimated occupancy of 35%) corresponds to the location of the third and fourth residues of acarbose in its complex with glucoamylase at pH 6. The position of high density (65% occupancy) corresponds to a new binding mode of an extended inhibitor to the active site of glucoamylase. Presented are possible causes for the binding of o-gfuco-dihydroacarbose in two conformations at the active site of glucoamylase at pH 4.

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“…The residues intervening between helices were in several tight turns. Using (3 1 F, I -2 IF, 1) maps and omit maps calculated with phases from the remaining atoms (coefficients IF, I exp iac) we compared this interpretation with structures selected from the database by the routine DGLP in TOM (Cambillau & Horjales, 1987). A related region from uteroglobulin suggested an alternative model that extended helices a-1 and a-3, allowing Pro 62 to introduce a distinct kink in helix a-3 (as shown in Fig.…”

Section: Refinement and Model Building Prolsq Refinementmentioning

confidence: 99%

Comparison of the crystal structures of genetically engineered human manganese superoxide dismutase and manganese superoxide dismutase from thermus thermophilus: Differences in dimer–dimer interaction

et al. 1993

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The three‐dimensional X‐ray structure of a recombinant human mitochondrial manganese superoxide dismutase (MnSOD) (chain length 198 residues) was determined by the method of molecular replacement using the related structure of MnSOD from Thermus thermophilus as a search model. This tetrameric human MnSOD crystallizes in space group P21212 with a dimer in the asymmetric unit (Wagner, U.G., Werber, M.M., Beck, Y., Hartman, J.R., Frolow, F., & Sussman, J.L., 1989, J. Mol. Biol. 206, 787–788). Refinement of the protein structure (3, 148 atoms with Mn and no solvents), with restraints maintaining noncrystallographic symmetry, converged at an R‐factor of 0.207 using all data from 8.0 to 3.2 Å resolution and group thermal parameters. The monomer–monomer interactions typical of bacterial Fe‐ and Mn‐containing SODs are retained in the human enzyme, but the dimer–dimer interactions that form the tetramer are very different from those found in the structure of MnSOD from T. thermophilus. In human MnSOD one of the dimers is rotated by 84° relative to its equivalent in the thermophile enzyme. As a result the monomers are arranged in an approximately tetrahedral array, the dimer–dimer packing is more intimate than observed in the bacterial MnSOD from T. thermophilus, and the dimers interdigitate. The metal—ligand interactions, determined by refinement and verified by computation of omit maps, are identical to those observed in T. thermophilus MnSOD.

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TOM: a FRODO subpackage for protein-ligand fitting with interactive energy minimization

Cited by 156 publications

References 20 publications

Comparison of the Heme-free and -bound Crystal Structures of Human Heme Oxygenase-1

Comparison of the Heme-free and -bound Crystal Structures of Human Heme Oxygenase-1

Refined structure for the complex of d‐gluco‐dihydroacarbose with glucoamylase from Aspergillus awamori var. X100 to 2.2 Å resolution: dual conformations for extended inhibitors bound to the active site of glucoamylase

Comparison of the crystal structures of genetically engineered human manganese superoxide dismutase and manganese superoxide dismutase from thermus thermophilus: Differences in dimer–dimer interaction

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