PROGRESS IN CHEMISTRY. balanol A X Computational Chemistry of Protein Kinase A and Its Inhibitor Balanol

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1 PROGRESS IN CHEMISTRY Vol. 22 No. 5 May2010 * PKA balanol A PKA X PKA PKA C R C balanol QM / MM A PKA balanol Q O QM / MM A X Computational Chemistry of Protein Kinase A and Its Inhibitor Balanol Jin Haixiao Yan Xiaojun Zhu Peng Key Laboratory of Marine BiotechnologyNingbo UniversityNingbo China Abstract Protein kinases regulate the signal transduction pathways in cell by phosphorylating the protein kinase substrateand they are important targets in drug design. Protein kinase A PKA is the first kinase that was obtained X-ray structure of its catalytic domainand is regarded as prototype for protein kinase superfamily. The progress in computational chemistry study of protein kinase A has been reviewed including the molecular dynamics simulation study of PKA holoenzyme and its C subunit and R subunit in aqueous solutionphosphoryl transfer mechanismthe binding free energy predicting and flexible docking of C subunit with its inhibitor balanol. Various computational approaches are applied to this systemincluding molecular dynamics simulationdockhomology modelingqm / MM. Key words protein kinase A PKA balanol molecular dynamics simulation dock QM / MM Contents 1 Introduction 2 Molecular dynamics simulation study on PKA 2. 1 Molecular dynamics simulation study on C subunit 2. 2 Modeling of the complex of C subunit and R subunit 2. 3 Molecular dynamics simulation study on R subunit 3 Phosphoryl transfer mechanism 4 Balanol 4. 1 Prediction of binding free energy 4. 2 Flexible protein-flexible ligand docking 4. 3 Mechanism of high selectivity of balanol analogue BD Functional role of structure water molecules in the recognition of C subunit and BD * No No. RCL Corresponding author yanxiaojun@ nbu. edu. cn

994 22 5 Conclusion and outlook 1 1 ATP 4 PKA γ 2 4 5 G 60 1 PKA camp Fig.

2 Conclusion and outlook 1 1 ATP 4 PKA γ G 60 1 PKA camp Fig. 1 The active catalytic subunits are released from the inactive PKA holoenzyme by binding to camp PKA A protein kinase A PKA 6 PKA PKA PKA camp campdependent protein kinase / PKA C 2 β small lobe camp α large lobe N 1 39 C camp camp ATP camp ATP camp protein kinase substrate PKS PKA PKA C 2 R 2 2 protein kinase inhibitor PKI C 2 R 1 loop activation PKA loop Thr197 C Ser338 RⅠ RⅠα RⅠβ RⅡ RⅡα RⅡβ R loop Thr197 PKA-ⅠPKA-Ⅱ PKA-Ⅰ PKA-Ⅱ 2 R C PKA 2 R A domain A B domain B 4 camp 2 R R C / C loop glycine-rich loop ATP C R 3 8 dimerization / docking C RⅠα AKAP A kinase anchoring 4 9 R protein PKA PKA camp A domain A B C 3 R 2 B / C helix R / camp nucleotide binding domainnbd R / C A B R / camp

5 PKA balanol 995 2 C ATP PKI PDB ID 1ATP C loop 3 R camp PDB ID 1RGS A B camp R PKI A B A ATP / Mg 2 + B / C camp pthr197 pser338 pthr197 phosphate-binding cassettepbc Trp260 Tyr371 α Glu261 Arg366

The small lobe is colored in magentathe glycine-rich loop within small lobe is shown in yellowthe large lobe is colored in brownand the dark green one is the protein kinase inhibitor.

pthr197 and pser338 is described as ball and stick and these residues formed hydrogen bond or salt bridge with pthr197 is represented in green ball and stick.

3 5 PKA balanol C ATP PKI PDB ID 1ATP C loop 3 R camp PDB ID 1RGS A B camp R PKI A B A ATP / Mg 2 + B / C camp pthr197 pser338 pthr197 phosphate-binding cassettepbc Trp260 Tyr371 α Glu261 Arg366 Glu200 Fig. 2 The crystal structure of C subunit binding to ATP and PKI PDB ID 1ATP. The small lobe is colored in magentathe glycine-rich loop within small lobe is shown in yellowthe large lobe is colored in brownand the dark green one is the protein kinase inhibitor. The ATP / Mg 2 + in the active site is in red ball and stick representation. pthr197 and pser338 is described as ball and stick and these residues formed hydrogen bond or salt bridge with pthr197 is represented in green ball and stick. The Cα atoms of main catalytic residues in phosphoryl transfer region are labeled in yellow ball model Arg241 Asp140 Lys240 Fig. 3 The crystal structure of R subunit binding to camp PDB ID 1RGS. The camp in domain A and B is in ball and stick representationthe domain A and domain B of R subunit is represented as dark teal and cyanrespectively the B / C helix within domain A is shown as redphosphatebinding cassette within the two domain is described as yellowtrp260and Tyr371 are labeled as green stick and van der Waals surfaceglu261 and Arg366 is shown as yellow stickglu200 and Arg241 is shown as magenta stick and Asp140 and Lys240 is shown as cyan stick R / C R / camp Glu200 Arg241 B / C Trp260 Tyr371 A B camp 4 R / C Glu200 Arg241 Glu261 Arg366 Asp140 Lys240 B / C Trp260 Tyr371 4 C RⅠα PDB ID camp camp PKA- 2QCS C R 3 Ⅰ B A Fig. 4 The crystal structure of C subunit and RⅠα subunit 10 camp B complex PDB ID 2QCS. C subunit is labeled as purple Glu261-Arg366 RⅠ ribbon and a van der Waals surfacethe R subunit is shown as that in figure PKA

4 R / C InRK 2 CDK2 C ADP AlF 3 loop C ATP PKA PKA PKA loop Thr197 C C C ATP C Thr197 pthr197 6 pthr197 C Cheng 12 balanol PKA C QM / MM balanol PKA Thr197 loop C / balanol pthr197 C C C balanol ATP C / ATP C balanol C / ppks amber 8 5 nm PKA 13 pthr197 C C His87 Lys189 Thr195 Arg165 balanol 2 2 PKA Thr197 loop 2. 1 C C PKA C ATP 14 C ATP PKI C / ATP / PKI C loop loop Tsigelny 11 amber 4. 1 C ATP C / ATP / PKI loop Thr197 PKA / Mg 2 ATP / substrate T197A Thr197 His87 C ATP ATP PKI amber 2. 2 C R - C ATP PKI ATP C R C Anand 15 loop C DOT R / C DOT loop R C PDB

5 5 PKA balanol 997 1RGS R ATP R C R C Ⅰ / A C R / C A camp 2 R / C 3 4 C R / C R Glu200 Arg241 Asp140 DOT R Lys C R / camp Glu200 C R Arg241 R / C 17 C loop R A loop Ⅱ RⅠα camp C R 2 camp RⅠα 18 B C RⅠα A C Ⅱ R / C RⅠα R / camp R loop C R RⅠ C 20 Ⅱ 2. 3 R C Glu200 Arg RⅠα C A R RⅠα C camp RⅠα PKA 2 3 RⅠα C RⅠα A R / C Ⅰ Ⅱ A R / R / camp C R B / C A B R / R A B / C C C B / C C R C Ⅰ C B / C R A R R / B R C 3 R C PKA C C ADP PKS C / ADP / AlF 3 / PKS 21 PDB ID 1L3R 23 ATP γ Gullingsrud 22 ADP RⅠα Ⅰ RⅠα Ⅱ R C Ⅲ 3 R R R / C Asp140 Lys240 ⅢRⅠα C

998 22 C / ATP / PKI ATP γ 27 Lys168 PDB ID 1ATP 24 5 Ala K cat 50 PKI loop glycine-rich loop KTLG 50 TG 52 SFG 55 RV Ser 23 loop PKA Asp166 Gly Ala Ser PKA Lys168 loop 5 C / ADP / AlF 3 / PKS PDB ID

6 C / ATP / PKI ATP γ 27 Lys168 PDB ID 1ATP 24 5 Ala K cat 50 PKI loop glycine-rich loop KTLG 50 TG 52 SFG 55 RV Ser 23 loop PKA Asp166 Gly Ala Ser PKA Lys168 loop 5 C / ADP / AlF 3 / PKS PDB ID Diaz 36 1L3R C / ATP / PKI PDB ID 1ATP Asp166 loop loop 10 20kcal / mol Henkelman 37 1ATP 1L3R Mg 2 + Fig. 5 The superposition of X-ray structure of the C / ADP / AlF 3 / PKS complex PDB ID 1L3R and the C / ATP / PKI complex PDB ID 1ATP. Glycine-rich loop and catalytic Cheng 38 Valiev 39 QM / MM loop are represented as line ribbon and flat ribbon C C respectively. The residues from 1ATP are shown as line and these residues from 1L3R are described as ball and QM C stickthe two Mg 2 + are labeled in ball model MM Asp166 Asp166 PKA loop 5 P Ser P Ser Lys168 Asp166 Ala V max 300 ATP ATP γ Lys168 PKS K m 25 Asp166 ATP γ P Ser Ser ATP 26 ph = 6 9 PKA Asp pk a < 5 Ser pk a = Ser53 Thr Gly Pro K 29 cat QM AM1 PM3 QM / MM Asp166 P Ser ATP γ Hirano 33 Cavalli kcal / mol Valiev 35 loop Ser53 loop Asp166 loop Ser53 Ser53 Lys168 ATP γ PKA

7 5 PKA balanol 999 Szarek 40 Mg 2 + Ⅱ Mg2 + Ⅰ Lys72 Asp kcal / mol kcal / mol kcal / mol kcal / mol Wong 45 C / balanol Lys168 Ser53Glu91 Asp184 Ser53 glycine- - rich loop kcal / mol QM / MM - Asp166 4 Balanol ATP Asp184 C ATP Thr183 H89 staurosporin balanol Balanol Verticillium balanoides 41 C / balanol 42 balanol balanol ATP 4 6 A ATP B C D loop Balanol PKA Cprotein kinase C PKC 43 Src ATP C / balanol Balanol 18 Wong 47 autodock balanol C C C / balanol C 6 Fig. 6 Balanol BD2 The chemical structures of balanol and BD2 390 Lys72 Asp184 Thr183 C / balanol Lys72 Thr183 Wang Wong 46 QM / MM / PBSA C C / balanol C C Hünenberger 44 balanol ATP C

8 BD2 Kovacs Zhao Sanner 50 FLIPDock flexible ligand-protein docking flexibility tree data structure PKA X autodock3. 05 C PKA C / adenosine / PKI PDB ID 1FMO PKA balanol - 1FMO C - FLIPDock QM / MM PKA Huang Wong 51 PKA balanol 4. 3 Balanol BD2 ATP Balanol 1993 ATP balanol BD2 6 PKA ATP PKA PKC BD2 PKA PKC / BD2 PKA / BD2 PKC / BD2 MM-GBSA PKA PKC BD BD2 B PKA PKC BD2 PKA Thr183 PKC Ala C BD2 C / BD2 C 3 C / BD nm C 3 C R camp 1 Johnson L NLewis R J. Chem. Rev Naviglio SCaraglia MAbbruzzese Aet al. Expert. Opin. Ther. Targets Murray A J. Sci. Signal art. no. re4 4 Taylor S SKim CCheng C Yet al. Biochim. Biophys. Acta Chiaradonna FBalestrieri CGaglio Det al. Front. Biosci Yonemoto WMcGlone M LGrant Bet al Protein Eng. 7 Knighton DZheng JTen Eyck Let al. Science Su YDostmann W RHerberg F Wet al Kim CCheng C YSaldanha S Aet al Science1995 Cell Herberg F WTaylor S SDostmann W R. Biochemistry1996

9 5 PKA balanol Tsigelny IGreenberg J PCox Set al Biopolymers Cheng Y HZhang Y KMcCammon J A. Protein Sci Jin H XWu T XJiang Y Jet al. J. Mol. Struct. Theochem Cheng XMa YMoore Met al. Proc. Natl. Acad. Sci Anand G SLaw DMandell J Get al. Proc. Natl. Acad. Sci. USA Tung C SWalsh D ATrewhella J. J. Biol. Chem Kim CVigil DAnand Get al. Eur. J Cell Biol Taylor S SYang JWu Jet al. Biochim. Biophys. Acta Iyer G HGarrod SWoods J V Let al. J. Mol. Biol Kim CXuong N HTaylor S S. Science Kumar SMa BTsai C Jet al. Protein Sci Gullingsrud JKim CTaylor S Set al. Structure MadhusudanAkamine PXuong N Het al. Nat. Struct. Biol Zheng JTrafny E AKnighton D Ret al. Acta Crystallogr. D Biol. Crystallogr Gibbs C SZoller M J. J. Biol. Chem Zhou JAdams J A. Biochemistry MadhusudanTrafny E AXuong N Het al Protein Sci. 28Hemmer WMcGlone MTsigelny Iet al. J. Biol. Chem Aimes R THemmer WTaylor S S. Biochemistry Hart J CSheppard D WHillier I Het al. Chem. Commun Hart J CHillier I HBurton N Aet al. J. Am. Chem. Soc Hutter M CHelms V. Protein Sci Hirano YHato MHoshino Tet al. J. Phys. Chem. B Cavalli ADe Vivo MRecanatini M. Chem. Commun Valiev MKawai RAdams J Aet al. J. Am. Chem. Soc Diaz NField M J. J. Am. Chem. Soc Henkelman GLaBute M XTung C Set al. Proc. Natl. Acad. Sci. USA Cheng YZhang YMcCammon J A. J. Am. Chem. Soc Valiev MYang JAdams J Aet al. J. Phys. Chem. B Szarek PDyguda-Kazimierowicz ETachibana Aet al. J. Phys. Chem. B Kulanthaivel PHallock Y FBoros Cet al. J. Am. Soc Chem. 42Narayana NDiller T CKoide Ket al. Biochemistry Setyawan JKoide KDiller T Cet al. Mol. Pharmacol Hünenberger P HHelms VNarayana Net al. Biochemistry Wong C FHünenberger P HAkamine Pet al. J. Med. Chem Wang MWong C F. J. Chem. Phys art. no Wong C FKua JZhang Yet al. Proteins Kovacs J ACavasotto C NAbagyan R J. et al. J. Comput. Theor. Nanosci Cavasotto C NKovacs J AAbagyan R A. J. Am. Chem. Soc Zhao YSanner M F. Proteins Huang ZWong C FWheeler R A. Proteins Akamine PMadhusudanBrunton L Let al Biochemistry 53 Jin H X Wu T X Yan X J. Acta Chimica Sinica Jin H XWu T XJiang Y Jet al. J. Mol. Struct. Theochem

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