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Homology modeling of G protein-coupled receptors

Homology modeling of G protein-coupled receptors. Aug 24~26, 2009 제 3 회 단백질 연구 발표회. Eo, Hae-Seok. School of Computational Sciences, KIAS. G protein-coupled receptors (1). Cell surface. G protein-coupled receptors (GPCRs) Transmembrane proteins

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Homology modeling of G protein-coupled receptors

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  1. Homology modeling of G protein-coupled receptors Aug 24~26, 2009 제3회 단백질 연구 발표회 Eo, Hae-Seok School of Computational Sciences, KIAS

  2. G protein-coupled receptors (1) Cell surface • G protein-coupled receptors (GPCRs) • Transmembrane proteins • The largest group ofproteins in the human genome, with more than 900 genes • Key controllers of diverse physiological processes (signal transduction) • More than half of all modern drugs are targeted at GPCRs

  3. G protein-coupled receptors (2) • G protein-coupled receptors (GPCRs) • Comprised of seven transmembrane α-helices linked by three alternating intracellular and extracellular loops, with an extracellular amino terminus and a cytoplasmic carboxy terminus

  4. G protein-coupled receptors (3) αgroup GPCRs (900~) Rhodopsin Prostaglandin receptor cluster Amine receptor cluster Opsin receptor cluster Melatonin receptor cluster MECA receptor cluster βgroup γgroup SOG receptor cluster MCH receptor cluster Chemokine receptor cluster δgroup MAS-related receptor cluster Glycoprotein receptor cluster Purine receptor cluster Olfactory receptor cluster Secretin • Classified by functions • Mainly predicted by sequence similarity • Orphan receptors Adhesion Glutamate Frizzled/Taste2

  5. Computational approaches for GPCR Function annotation & Classification • Mainly classified by primary or secondary structural information • Tertiary structural information is crucial for function annotation and classification. • Homology modeling • - Xiang-Qun Xie et al. (2003) Proteins 53: 307-319 • - Caterina Bissantz et al. (2004) J Chem Inf Comput Sci 44: 1162-1176 • - Robert Kiss et al. (2004) Eur J Med Chem 39: 959-967 • - Mateusz Nowak et al. (2006) J Med Chem 49: 205-214 • - Amaury Farce et al. (2008) Eur J Med Chem 43: 1926-1944 • - Akinori Hirashima et al. (2008) Comput Biol Chem 32: 185-190 • - A. Saxena et al. (2008) SAR QSAR Environ Res 19: 11-25 • - Chiara Parravicini et al. (2008) BMC Bioinformatics 9: 263 • - Benny Keissl et al. (2009) J Med Chem Epub • Skolnick group (2006) • - Threading assembly refinement (TASSER) method • - 907 GPCRs in the human genome

  6. GPCR Homology Modeling (1) GPCRs solved to date

  7. GPCR Homology Modeling (2) Modeling Procedure (CASP8) Target Models 2nd • 4 solved structures + α FoldFinder & 3D-Jury QA & structure clustering Fold Recognition • AVG over the 100 models of each MSA for measuring the Q of the alignment • Select the winning MSAs • Select best 5 models by structure clustering • Alignments from the local minima (100) Multiple Sequence Alignment MSACSA Chain building ModellerCSA (100 3D for each MSA) (500-1000 models in total) 1st Model Quality Assessment (5-10개 MSA 선택) Modeller (25개/MSA) Chain building • QA for measuring the quality of each single model • AVG over the 25 models of each MSA for measuring the Q of the alignment

  8. GPCR Homology Modeling (3) FoldFinder & 3D-Jury Chain building ModellerCSA (100 3D for each MSA) (500-1000 models in total) Fold Recognition • • List 1 • List 2 • List 3 • List # And / Or 1st MSACSA Multiple Sequence Alignment 1st Model Quality Assessment (5-10개 MSA 선택) MSA Quality Assessment (5-10개 MSA 선택) • • Structural Alignment • Structural Information Modeller (25개/MSA) Chain building

  9. 감사합니다.

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