Homology modeling of G protein-coupled receptorsAug 24~26, 2009 3 Eo, Hae-SeokSchool of Computational Sciences, KIAS

G protein-coupled receptors (1)G protein-coupled receptors (GPCRs)Transmembrane proteinsThe largest group of proteins in the human genome, with more than 900 genesKey controllers of diverse physiological processes (signal transduction)More than half of all modern drugs are targeted at GPCRsCell surface

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

G protein-coupled receptors (3)GPCRs(900~)RhodopsinSecretinAdhesion GlutamateFrizzled/Taste2groupgroupgroupgroupProstaglandin receptor cluster Amine receptor clusterOpsin receptor clusterMECA receptor clusterSOG receptor clusterMCH receptor clusterChemokine receptor clusterMAS-related receptor clusterGlycoprotein receptor clusterPurine receptor clusterOlfactory receptor clusterMelatonin receptor cluster Classified by functions Mainly predicted by sequence similarity Orphan receptors

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

GPCR Homology Modeling (1)GPCRs solved to date

Sequence Identity (%) / Sequence Similarity (%) / RMSD ()1U192RH12VT43EMLBovine rhodopsin (1U19)100% / 100% / 0.0 18% / 36% / 2.118% / 37% / 2.118% / 35% / 2.4Human 2AR (2RH1)100% / 100% / 0.064% / 79% / 0.729% / 44% / 2.1Turkey 1AR (2VT4)100% / 100% / 0.031% / 47% / 2.1Human A2A-adenosine (3EML)100% / 100% / 0.0

GPCR Homology Modeling (2)Modeling Procedure (CASP8)TargetFoldFinder & 3D-JuryFold Recognition 4 solved structures +

MSACSAMultiple Sequence Alignment Alignments from the local minima (100)

Modeller (25/MSA)Chain buildingModel Quality Assessment(5-10 MSA )1stModellerCSA(100 3D for each MSA)(500-1000 models in total)Chain buildingQA & structure clustering2ndModels QA for measuring the quality of each single model

AVG over the 25 models of each MSA for measuring the Q of the alignment 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

GPCR Homology Modeling (3)FoldFinder & 3D-JuryFold RecognitionMSACSAMultiple Sequence AlignmentMSA Quality Assessment(5-10 MSA )1stModellerCSA(100 3D for each MSA)(500-1000 models in total)Chain building List 1 List 2 List 3 List # Structural Alignment

Structural InformationModeller (25/MSA)Chain buildingModel Quality Assessment(5-10 MSA )1stAnd / Or

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