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Crystal structures of the S6K1 kinase domain in complexes with inhibitors.

Niwa H, Mikuni J, Sasaki S, Tomabechi Y, Honda K, Ikeda M, Ohsawa N, Wakiyama M, Handa N, Shirouzu M, Honma T, Tanaka A, Yokoyama S - J. Struct. Funct. Genomics (2014)

Bottom Line: Compound F179, with a carbonyl group in the middle of the molecule, altered the αC helix conformation by interacting with the invariant Lys123.Compounds F176 and F177 bound slightly distant from the hinge region, and their sulfoamide groups formed polar interactions with the protein.The structural features required for the specific binding of inhibitors are discussed.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, 230-0045, Japan.

ABSTRACT
Ribosomal protein S6 kinase 1 (S6K1) is a serine/threonine protein kinase that plays an important role in the PIK3/mTOR signaling pathway, and is implicated in diseases including diabetes, obesity, and cancer. The crystal structures of the S6K1 kinase domain in complexes with staurosporine and the S6K1-specific inhibitor PF-4708671 have been reported. In the present study, five compounds (F108, F109, F176, F177, and F179) were newly identified by in silico screening of a chemical library and kinase assay. The crystal structures of the five inhibitors in complexes with the S6K1 kinase domain were determined at resolutions between 1.85 and 2.10 Å. All of the inhibitors bound to the ATP binding site, lying along the P-loop, while the activation loop stayed in the inactive form. Compound F179, with a carbonyl group in the middle of the molecule, altered the αC helix conformation by interacting with the invariant Lys123. Compounds F176 and F177 bound slightly distant from the hinge region, and their sulfoamide groups formed polar interactions with the protein. The structural features required for the specific binding of inhibitors are discussed.

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Interactions of the S6K1KD·F176 complex. a Crystallographic two-fold related S6K1KD·F176 complexes. One molecule is colored in the same manner as in Fig. 2a. The other complex is colored gray. Interacting residues are shown as orange sticks. b Close-up view of the interface. c Interactions of the inhibitor, Tyr102, zinc ion, and phosphorylated Thr252 (stereoview). Interacting residues are shown as sticks, colored in the same manner as in (a)
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Fig5: Interactions of the S6K1KD·F176 complex. a Crystallographic two-fold related S6K1KD·F176 complexes. One molecule is colored in the same manner as in Fig. 2a. The other complex is colored gray. Interacting residues are shown as orange sticks. b Close-up view of the interface. c Interactions of the inhibitor, Tyr102, zinc ion, and phosphorylated Thr252 (stereoview). Interacting residues are shown as sticks, colored in the same manner as in (a)

Mentions: In the S6K1KD·F176 crystal, the complex molecule contacts the symmetry-related molecule, with their activation loops facing each other, across one of the dyad axes of the C2 space group (Fig. 5a). At the interface (Fig. 5b), Thr248 in the activation loop interacts with Asp246 in the activation loop and Arg298 in αG of the other molecule. In addition, Asn133 in the loop between αB and αC interacts with Asp303 in αG of the other molecule.Fig. 5


Crystal structures of the S6K1 kinase domain in complexes with inhibitors.

Niwa H, Mikuni J, Sasaki S, Tomabechi Y, Honda K, Ikeda M, Ohsawa N, Wakiyama M, Handa N, Shirouzu M, Honma T, Tanaka A, Yokoyama S - J. Struct. Funct. Genomics (2014)

Interactions of the S6K1KD·F176 complex. a Crystallographic two-fold related S6K1KD·F176 complexes. One molecule is colored in the same manner as in Fig. 2a. The other complex is colored gray. Interacting residues are shown as orange sticks. b Close-up view of the interface. c Interactions of the inhibitor, Tyr102, zinc ion, and phosphorylated Thr252 (stereoview). Interacting residues are shown as sticks, colored in the same manner as in (a)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4125821&req=5

Fig5: Interactions of the S6K1KD·F176 complex. a Crystallographic two-fold related S6K1KD·F176 complexes. One molecule is colored in the same manner as in Fig. 2a. The other complex is colored gray. Interacting residues are shown as orange sticks. b Close-up view of the interface. c Interactions of the inhibitor, Tyr102, zinc ion, and phosphorylated Thr252 (stereoview). Interacting residues are shown as sticks, colored in the same manner as in (a)
Mentions: In the S6K1KD·F176 crystal, the complex molecule contacts the symmetry-related molecule, with their activation loops facing each other, across one of the dyad axes of the C2 space group (Fig. 5a). At the interface (Fig. 5b), Thr248 in the activation loop interacts with Asp246 in the activation loop and Arg298 in αG of the other molecule. In addition, Asn133 in the loop between αB and αC interacts with Asp303 in αG of the other molecule.Fig. 5

Bottom Line: Compound F179, with a carbonyl group in the middle of the molecule, altered the αC helix conformation by interacting with the invariant Lys123.Compounds F176 and F177 bound slightly distant from the hinge region, and their sulfoamide groups formed polar interactions with the protein.The structural features required for the specific binding of inhibitors are discussed.

View Article: PubMed Central - PubMed

Affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, 230-0045, Japan.

ABSTRACT
Ribosomal protein S6 kinase 1 (S6K1) is a serine/threonine protein kinase that plays an important role in the PIK3/mTOR signaling pathway, and is implicated in diseases including diabetes, obesity, and cancer. The crystal structures of the S6K1 kinase domain in complexes with staurosporine and the S6K1-specific inhibitor PF-4708671 have been reported. In the present study, five compounds (F108, F109, F176, F177, and F179) were newly identified by in silico screening of a chemical library and kinase assay. The crystal structures of the five inhibitors in complexes with the S6K1 kinase domain were determined at resolutions between 1.85 and 2.10 Å. All of the inhibitors bound to the ATP binding site, lying along the P-loop, while the activation loop stayed in the inactive form. Compound F179, with a carbonyl group in the middle of the molecule, altered the αC helix conformation by interacting with the invariant Lys123. Compounds F176 and F177 bound slightly distant from the hinge region, and their sulfoamide groups formed polar interactions with the protein. The structural features required for the specific binding of inhibitors are discussed.

Show MeSH
Related in: MedlinePlus