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Crystal structure of human ALKBH7 in complex with alpha-ketoglutarate and Mn(II)Crystal structure of human ALKBH7 in complex with alpha-ketoglutarate and Mn(II)
Structural highlights
Function[ALKB7_HUMAN] Probable dioxygenase required to induce programmed necrosis in response to DNA damage caused by cytotoxic alkylating agents. Acts by triggering the collapse of mitochondrial membrane potential and loss of mitochondrial function that leads to energy depletion and cell death [1]. ALKBH7-mediated necrosis is probably required to prevent the accumulation of cells with DNA damage. Does not display DNA demethylase activity. Involved in fatty acid metabolism.[2] Publication Abstract from PubMedALKBH7 is the mitochondrial AlkB family member that is required for alkylation- and oxidation-induced programmed necrosis. In contrast to the protective role of other AlkB family members after suffering alkylation-induced DNA damage, ALKBH7 triggers the collapse of mitochondrial membrane potential and promotes cell death. Moreover, genetic ablation of mouse Alkbh7 dramatically increases body weight and fat mass. Here, we present crystal structures of human ALKBH7 in complex with Mn(II) and alpha-ketoglutarate at 1.35 A or N-oxalylglycine at 2.0 A resolution. ALKBH7 possesses the conserved double-stranded beta-helix fold that coordinates a catalytically active iron by a conserved HX(D/E) ... Xn ... H motif. Self-hydroxylation of Leu-110 was observed, indicating that ALKBH7 has the potential to catalyze hydroxylation of its substrate. Unlike other AlkB family members whose substrates are DNA or RNA, ALKBH7 is devoid of the "nucleotide recognition lid" which is essential for binding nucleobases, and thus exhibits a solvent-exposed active site; two loops between beta-strands beta6 and beta7 and between beta9 and beta10 create a special outer wall of the minor beta-sheet of the double-stranded beta-helix and form a negatively charged groove. These distinct features suggest that ALKBH7 may act on protein substrate rather than nucleic acids. Taken together, our findings provide a structural basis for understanding the distinct function of ALKBH7 in the AlkB family and offer a foundation for drug design in treating cell death-related diseases and metabolic diseases. The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism.,Wang G, He Q, Feng C, Liu Y, Deng Z, Qi X, Wu W, Mei P, Chen Z J Biol Chem. 2014 Oct 3;289(40):27924-36. doi: 10.1074/jbc.M114.590505. Epub 2014, Aug 13. PMID:25122757[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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