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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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Conformational changes in the S6K1KD·F179 complex (stereoview). Superimposition of S6K1KD·F179 (yellow) and S6K1KD·PF-4708671 (cyan)
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Fig4: Conformational changes in the S6K1KD·F179 complex (stereoview). Superimposition of S6K1KD·F179 (yellow) and S6K1KD·PF-4708671 (cyan)

Mentions: In the S6K1KD·F179 complex structure, the carbonyl group in the middle of the inhibitor interacts with the Nε of Lys123 (Fig. 3d). This is the invariant lysine residue that interacts with Glu143 in helix αC, in the active form of the kinases [27]. In the other S6K1KD complexes in this study, Lys123 interacts with Glu143. The Nε atom of Lys123 in the S6K1KD·F179 structure moves by 3.0 Å towards the carbonyl group, as compared with the S6K1KD·PF-4708671 structure. Along with the rotation, helix αC moves down by about 3 Å, and thus Glu143 can hydrogen bond with the nitrogen atom of Gly238 (Fig. 4). Ala134 and Lys135 form the N-terminal cap of helix αC in the complex structures with PF-4708671, F176, and F177, where the side chain of Asp136 interacts with the hydroxyl group of Tyr102 in the P-loop. In the S6K1KD·F179 complex structure, however, Ala134 and Lys135 do not adopt the helical conformation and Asp136 moves away from Tyr102. Instead, the carbonyl oxygen atom of Asn133 interacts with Tyr102 (Fig. 4).Fig. 4


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)

Conformational changes in the S6K1KD·F179 complex (stereoview). Superimposition of S6K1KD·F179 (yellow) and S6K1KD·PF-4708671 (cyan)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Conformational changes in the S6K1KD·F179 complex (stereoview). Superimposition of S6K1KD·F179 (yellow) and S6K1KD·PF-4708671 (cyan)
Mentions: In the S6K1KD·F179 complex structure, the carbonyl group in the middle of the inhibitor interacts with the Nε of Lys123 (Fig. 3d). This is the invariant lysine residue that interacts with Glu143 in helix αC, in the active form of the kinases [27]. In the other S6K1KD complexes in this study, Lys123 interacts with Glu143. The Nε atom of Lys123 in the S6K1KD·F179 structure moves by 3.0 Å towards the carbonyl group, as compared with the S6K1KD·PF-4708671 structure. Along with the rotation, helix αC moves down by about 3 Å, and thus Glu143 can hydrogen bond with the nitrogen atom of Gly238 (Fig. 4). Ala134 and Lys135 form the N-terminal cap of helix αC in the complex structures with PF-4708671, F176, and F177, where the side chain of Asp136 interacts with the hydroxyl group of Tyr102 in the P-loop. In the S6K1KD·F179 complex structure, however, Ala134 and Lys135 do not adopt the helical conformation and Asp136 moves away from Tyr102. Instead, the carbonyl oxygen atom of Asn133 interacts with Tyr102 (Fig. 4).Fig. 4

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