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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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Inhibitor binding (stereoviews). a S6K1KD·PF-4708671 in this study, b S6K1KD·F108, c S6K1KD·F109, d S6K1KD·F179, e S6K1KD·F176, f S6K1KD·F177. In (a)–(f), the protein residues are colored cyan, and the residues in the P-loop and the strands β1 and β2 are green. Inhibitors are shown in salmon. The simulated-annealing composite omit maps (2mFo-DFc) are contoured at 1.2σ and depicted around the inhibitors (green mesh) and protein residues (gray mesh). These interactions were analyzed with LIGPLOT [28] and by manual inspection. g Superimposed bound inhibitors (stereoview). The color scheme is the same as in Fig. 2b. The backbones of the hinge region are also shown, with the same color scheme
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Fig3: Inhibitor binding (stereoviews). a S6K1KD·PF-4708671 in this study, b S6K1KD·F108, c S6K1KD·F109, d S6K1KD·F179, e S6K1KD·F176, f S6K1KD·F177. In (a)–(f), the protein residues are colored cyan, and the residues in the P-loop and the strands β1 and β2 are green. Inhibitors are shown in salmon. The simulated-annealing composite omit maps (2mFo-DFc) are contoured at 1.2σ and depicted around the inhibitors (green mesh) and protein residues (gray mesh). These interactions were analyzed with LIGPLOT [28] and by manual inspection. g Superimposed bound inhibitors (stereoview). The color scheme is the same as in Fig. 2b. The backbones of the hinge region are also shown, with the same color scheme

Mentions: The inhibitor binding modes of S6K1KD, shown in Fig. 3a–f, share some common features. One or two aromatic rings, shown at the bottom of each panel in Fig. 1, face the hinge region of the kinase domain, and are surrounded by hydrophobic residues, such as Leu97 and Ala121 at the top and Met225 at the bottom. The inhibitor molecules form extensive hydrophobic and van der Waals interactions between strands β1 and β2, and interact with their residues, such as Leu97 and Val105. These β-strands are just before and after the P-loop in the sequence. The aromatic ring(s) at the other end of the inhibitor molecules reach or approach the P-loop side at the top and Lys241 at the bottom. Thus, the inhibitor molecules extend from the hinge region, lie alongside the β1–P-loop–β2 moiety, and bend in the middle. The inhibitors are not bound in the ATP phosphate-binding site, which is occupied by the side chain of Lys241. Additional details for each inhibitor are described, as follows.Fig. 3


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)

Inhibitor binding (stereoviews). a S6K1KD·PF-4708671 in this study, b S6K1KD·F108, c S6K1KD·F109, d S6K1KD·F179, e S6K1KD·F176, f S6K1KD·F177. In (a)–(f), the protein residues are colored cyan, and the residues in the P-loop and the strands β1 and β2 are green. Inhibitors are shown in salmon. The simulated-annealing composite omit maps (2mFo-DFc) are contoured at 1.2σ and depicted around the inhibitors (green mesh) and protein residues (gray mesh). These interactions were analyzed with LIGPLOT [28] and by manual inspection. g Superimposed bound inhibitors (stereoview). The color scheme is the same as in Fig. 2b. The backbones of the hinge region are also shown, with the same color scheme
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Fig3: Inhibitor binding (stereoviews). a S6K1KD·PF-4708671 in this study, b S6K1KD·F108, c S6K1KD·F109, d S6K1KD·F179, e S6K1KD·F176, f S6K1KD·F177. In (a)–(f), the protein residues are colored cyan, and the residues in the P-loop and the strands β1 and β2 are green. Inhibitors are shown in salmon. The simulated-annealing composite omit maps (2mFo-DFc) are contoured at 1.2σ and depicted around the inhibitors (green mesh) and protein residues (gray mesh). These interactions were analyzed with LIGPLOT [28] and by manual inspection. g Superimposed bound inhibitors (stereoview). The color scheme is the same as in Fig. 2b. The backbones of the hinge region are also shown, with the same color scheme
Mentions: The inhibitor binding modes of S6K1KD, shown in Fig. 3a–f, share some common features. One or two aromatic rings, shown at the bottom of each panel in Fig. 1, face the hinge region of the kinase domain, and are surrounded by hydrophobic residues, such as Leu97 and Ala121 at the top and Met225 at the bottom. The inhibitor molecules form extensive hydrophobic and van der Waals interactions between strands β1 and β2, and interact with their residues, such as Leu97 and Val105. These β-strands are just before and after the P-loop in the sequence. The aromatic ring(s) at the other end of the inhibitor molecules reach or approach the P-loop side at the top and Lys241 at the bottom. Thus, the inhibitor molecules extend from the hinge region, lie alongside the β1–P-loop–β2 moiety, and bend in the middle. The inhibitors are not bound in the ATP phosphate-binding site, which is occupied by the side chain of Lys241. Additional details for each inhibitor are described, as follows.Fig. 3

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