Histone mechanism

The cis-acting elements that decrease or repress the expression of specific genes have also been identified. Because fewet of these elements have been smdied, it is not possible to fotmulate genetalizations about their mechanism of action—though again, as for gene activation, chromatin level covalent modifications of histones and other proteins by (repressor)-recruited multisubunit corepressors have been imphcated. 

These macromolecules include histones, ribosomal proteins and ribosomal subunits, ttansctiption factors, and mRNA molecules. The transport is bidirectional and occurs through the nucleat pote complexes (NPCs). These are complex stmctures with a mass approximately 30 times that of a ribosome and are composed of about 100 diffetent proteins. The diameter of an NPC is approximately 9 run but can increase up to ap-ptoximately 28 nm. Molecules smaller than about 40 kDa can pass through the channel of the NPC by diffusion, but special translocation mechanisms exist fot latget molecules. These mechanisms are under intensive investigation, but some important features have already emerged. 

Labbe, J. C., Picard, A. Peaucellier, G., Cavadore, J. C., Nurse, P., and Doree, M. (1989b). Purification of MPF from starfish identification as the HI histone kinase p34cpossible mechanism for its periodic activation. Cell 57 253-263. 

Sung, M. T., and Dixon, G. H. (1970). Modification of histones during spermiogenesis in trout a molecular mechanism for altering histone binding to DNA. Proc. Natl. Acad. Sci. USA 67 1616-1623. 

AB INITIO QUANTUM MECHANICAL/MOLECULAR MECHANICAL STUDIES OF HISTONE MODIFYING ENZYMES... 

In the nuclei of all eukaryotic cells, DNA is tightly wrapped around an octamer of histone proteins and is compacted into a dense structure known as chromatin. In order to access the genetic information which is required in numerous essential cellular processes including DNA replication, gene expression and DNA repair, chromatin needs to be partially unwound. One important mechanism to regulate chromatin structure and thus to control the access of the genomic DNA is through histone modifications [1-6]. The histone octamer is composed of two copies of H2A, H2B, H3 and H4 core histone proteins. Their tails, that protrude out of the surface of the... 

In our simulations of histone modifying enzymes, the computational approaches centered on the pseudobond ab initio quantum mechanical/molecular mechanical (QM/MM) approach. This approach consists of three major components [20,26-29] a pseudobond method for the treatment of the QM/MM boundary across covalent bonds, an efficient iterative optimization procedure which allows for the use of the ab initio QM/MM method to determine the reaction paths with a realistic enzyme environment, and a free energy perturbation method to take account... 

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

ENZYME MECHANISM AND CATALYSIS OF HISTONE LYSINE METHYLATION [49,50]... 

With the characterized mechanism, the next key question is the origin of its catalytic power. A prerequisite for this investigation is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio QM/MM approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9... 

Corminboeuf C, Hu P, Tuckerman ME, Zhang Y (2006) Unexpected catalytic mechanism for histone deacetylase suggested by a density functional theory QM/MM study. J Am Chem Soc 128 4530 1531... 

Hu P, Zhang Y (2006) Catalytic mechanism and product specificity of the histone lysine methyl-transferase set7/9 An ab initio QM/MM-FE study with multiple initial structures. J Am Chem Soc... 

Wang S, Hu P, Zhang Y (2007) Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis the case of histone lysine methyltransferase set7/9. J Phys Chem B ASAP... 

Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ (2003) Structure and catalytic mechanism of the human histone methyltransferase set7/9. Nature 421 652-656... 

Kwon T, Chang JH, Kwak E, Lee CW, Joachimiak A, Kim YC, Lee JW, Cho Y (2003) Mechanism of histone lysine methyl transfer revealed by the structure of set7/9-adomet. EMBO J., 22 292-303... 

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