Generation of 3D templates of active sites of proteins with rigid prosthetic groups

Article English OPEN
Nebel, Jean-Christophe (2006)

MOTIVATION: With the increasing availability of protein structures, the generation of biologically meaningful 3D patterns from the simultaneous alignment of several protein structures is an exciting prospect: active sites could be better understood, protein functions and protein 3D structures could be predicted more accurately. Although patterns can already be generated at the fold and topological levels, no system produces high-resolution 3D patterns including atom and cavity positions. To address this challenge, our research focuses on generating patterns from proteins with rigid prosthetic groups. Since these groups are key elements of protein active sites, the generated 3D patterns are expected to be biologically meaningful. RESULTS: In this paper, we present a new approach which allows the generation of 3D patterns from proteins with rigid prosthetic groups. Using 237 protein chains representing proteins containing porphyrin rings, our method was validated by comparing 3D templates generated from homologues with the 3D structure of the proteins they model. Atom positions were predicted reliably: 93% of them had an accuracy of 1.00 A or less. Moreover, similar results were obtained regarding chemical group and cavity positions. Results also suggested our system could contribute to the validation of 3D protein models. Finally, a 3D template was generated for the active site of human cytochrome P450 CYP17, the 3D structure of which is unknown. Its analysis showed that it is biologically meaningful: our method detected the main patterns of the cytochrome P450 superfamily and the motifs linked to catalytic reactions. The 3D template also suggested the position of a residue, which could be involved in a hydrogen bond with CYP17 substrates and the shape and location of a cavity. Comparisons with independently generated 3D models comforted these hypotheses. AVAILABILITY: Alignment software (Nestor3D) is available at
  • References (35)
    35 references, page 1 of 4

    Ahmed,S. (2004) The use of the novel substrate-heme complex approach in the derivation of a representation of the active site of the enzyme complex 17alpha-hydroxylase and 17,20-lyase. Biochem. Biophys. Res. Commun., 316, 595-598.

    Berman,H.M. et al. (2000) The Protein Data Bank. Nucleic Acids Res., 28, 235-242.

    Bertini,I. et al. (2004) NMR-validated structural model for oxidized Rhodopseudomonas palustris cytochrome c(556). J. Biol. Inorg. Chem., 9, 224-230.

    Brady,G.P. and Stouten,P.F.W. (2000) Fast prediction and visualization of protein binding pockets with PASS. J. Computer-Aided Mol. Design, 14, 383-401.

    Campbell,S.J. et al. (2003) Ligand binding: functional site location, similarity and docking. Curr. Opin. Struct. Biol., 13, 389-395.

    Cicek,M.S. et al. (2004) Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR. Prostate, 59, 69-76.

    Douglas,J.A. et al. (2005) Identifying susceptibility genes for prostate cancer-a family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-beta. Cancer Epidemiol. Biomarkers Prev., 14, 2035-2039.

    Eyal,E. et al. (2005) The limit of accuracy of protein modeling: influence of crystal packing on protein structure. J. Mol. Biol., 351, 431-442.

    Falquet,L. et al. (2002) The PROSITE database, its status in 2002. Nucleic Acids Res., 30, 235-238.

    Gibrat,J.F. et al. (1996) Surprising similarities in structure comparison. Curr. Opin. Struct. Biol., 6, 377-385.

  • Bioentities (3)
    1akd Protein Data Bank
    1s05 Protein Data Bank
    1u5u Protein Data Bank
  • Metrics
    views in OpenAIRE
    views in local repository
    downloads in local repository

    The information is available from the following content providers:

    From Number Of Views Number Of Downloads
    Kingston University Research Repository - IRUS-UK 0 6
Share - Bookmark