期刊
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
卷 69, 期 -, 页码 266-275出版社
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S0907444912045520
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资金
- University of Virginia Cancer Center through the NCI Cancer Center [P30 CA44579]
- National Institutes of Health [R01 GM086457]
- US Department of Energy, Office of Science and Office of Basic Energy Sciences [W-31-109-Eng-38]
Members of the RSK family of kinases constitute attractive targets for drug design, but a lack of structural information regarding the mechanism of selective inhibitors impedes progress in this field. The crystal structure of the N-terminal kinase domain (residues 45-346) of mouse RSK2, or RSK2(NTKD), has recently been described in complex with one of only two known selective inhibitors, a rare naturally occurring flavonol glycoside, kaempferol 3-O-(3 '',4 ''-di-O-acetyl-alpha-L-rhamnopyranoside), known as SL0101. Based on this structure, it was hypothesized that quercitrin (quercetin 3-O-alpha-L-rhamnopyranoside), a related but ubiquitous and inexpensive compound, might also act as an RSK inhibitor. Here, it is demonstrated that quercitrin binds to RSK2(NTKD) with a dissociation constant (K-d) of 5.8 mu M as determined by isothermal titration calorimetry, and a crystal structure of the binary complex at 1.8 angstrom resolution is reported. The crystal structure reveals a very similar mode of binding to that recently reported for SL0101. Closer inspection shows a number of small but significant differences that explain the slightly higher K-d for quercitrin compared with SL0101. It is also shown that quercitrin can effectively substitute for SL0101 in a biological assay, in which it significantly suppresses the contractile force in rabbit pulmonary artery smooth muscle in response to Ca2+.
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