蛋白質構造データバンクのデータ検証
高度化・統合化と創薬研究
栗栖源嗣
大阪大学蛋白質研究所

wwpdb.org

Licensed under a Creative Commons表示4.0国際ライセンス(c)2018栗栖 源嗣（大阪大学蛋白質研究所）0https://pdbj.org
生体高分子の3次元構造（形）に関する情報を集めた国際的データベース
1971年からのデータが集積され，情報は無償で利用できる．運営は各国（米国，欧州，日本）の政府機関による研究費用でまかなわれている．2003年からは国際組織wwPDBとして活動している（PDBjは創立メンバー）．
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PDBjで提供するFile Format• Experimental Data (X-ray, NMR, 3DEM=EMDB)• Validation Report (PDF, XML, RDF)

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wwPDBにおけるRDF化の経緯
wwPDB/RDF
http://rdf.wwpdb.org/

Kinjo et al. (2012) Nucl. Acids Res. 40, D453-D460.
Yokochi et al. (2016) J. Biomed. Semantics, 7:16.
Kinjo et al. (2012) Nucl. Acids Res. 40, D453D460.
Cryo-EM
X-ray Structure

BMRB/RDF
http://bmrbpub.protein.osaka-u.ac.jp
NMR Structure

SAXS

Large
Complex

Sequence

In UniProt RDF:

Exp. Information(X-ray, NMR, EM, etc) PPI (interaction)

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PDBｊは日本を中心にアジア地区からのデータ登録に責任を持つ

Americas,
Oceania

Europe,AfricaAsia

deposit.wwpdb.org
引き続き，アジア地区のデータ登録とデータ検証に責任を持つ．
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創薬研究に重要な化合物情報

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PDBj-Mineの高度化
BIRD/PRDの検索が可能になっています。

解析精度の検索には分解能を指標にするしか有りませんでした。Example1: Gleevec using PDBj-Mine7

Explore 1T46: Gleevec using PDBj-Mine (cont.)8

Eelectron Density map (Molmil)

9Explore 1T46: Gleevec using PDBj-Mine (cont.)10

創薬研究に重要な化合物情報の検証
 Batch search against ChemicalComponent Dictionary withautomated CCD ID assignment
 Captures and displays authorprovided chemical information
 Comparison panel
 2D and 3D views of ligand
for review
Deposited instance from ID assignment
coordinates (left) and the closest
match in the dictionary (right)
 Display of local ligand electron
density fitLocal ligand density display (1.5 sigma omit map)
Top: REA in entry 1CBS with LLDF=1.31 (RSR=0.10, CC=0.95)
Bottom: TMP in entry 3HW4 with LLDF=6.77 (RSR=0.41, CC=0.70)
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wwPDBのデータ検証レポート
X-ray/EM/NMR

X-ray• Structure factor & electron density• Geometric & conformational• Wilson plot, outliers, tNCS
• bond, angle, planarity• wrong symmetry• protein backbone conformation• twinning• protein side-chain conformation• agreement (Rfree, RSR, RSCC)• Atomic & molecular interaction• all-atom contacts• under packingNMR• hydrogen bond quality• Chemical shifts• Non-protein• completeness• nucleic acids (RNA pucker, suite)• outliers• carbohydrates (N-glycan core)• estimated reference error• ligands (CSD)• random coil index• ions & other solvent• Structure ensembles• Incomplete model (e.g. CA_ONLY)• representative model (medoid)• domain detection

Caveat:LLDF (Local Ligand Density Fit) has been replaced by a combination of RSR(Real-space R factor) > 0.4 and RSCC (Real-space correlations coefficient) <0.8 since this March.

データ検証レポートの高度化
データの信頼性をマシン（AI）が判断できるようになり，PDBのデータ統合化には極めて重要．

※データ検証ファイルのRDF化

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wwPDB validation reports (XML)

Entry-level validation information:
Percentiles, overall validation metrics (e.g. Rfree), statistics.

Residue-level validation information:
Geometric outliers, torsion angles, RSR, RSRZ, clash score, occupancy
validation report of modeled subgroups (residues) repeat…

Entity-level validation information: Percentiles
validation report of modeled entities repeat…

PDBML-validation and wwPDB/RDF-validation

PostgreSQL dump image:category

description

size (GB)pdbx_dcc_map

output of MAPMAN used by DCC (RSR, RSCC, LLDF)

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pdbx_poly_seq_scheme

residue nomenclature mapping for polymer entities

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struct_mon_prot

structure properties of a protein

6entity_poly_seq

sequence of monomers in a polymer2

pdbx_validate_close_contact

close contact with regard to the distance expected2

https://bmrbpub.pdbj.org

SPARQL endpoint contains
wwPDB/RDF-validation graphhttps://bmrbpub.pdbj.org

Example2:Search wwPDB/RDF-validation
Search all enzyme-ligand complexes of which real space R-factor (RSR) of ligand is less than 10%.
(showing only essential part of about 30 line-SPARQL query)
PREFIX PDBov: <https://rdf.wwpdb.org/schema/pdbx-validation-v1.owl#>
SELECT ?PDB_ID ?enzyme ?ligand ?comp_id MIN(?RSR AS ?minRSR)FROM <http://rdf.wwpdb.org/pdb-validation>
WHERE {
?entity PDBov:link_to_enzyme ?link_to_enzyme ;✍ selection of enzyme
PDBov:entity.pdbx_description ?enzyme ;PDBov:of_datablock ?datablock .
BIND (SUBSTR(STR(?datablock),38,4) AS ?PDB_ID)…
FILTER (?ligand != "water" && !STRENDS(?ligand, "ION"))…

✍ ligand selection: non-polymer,?dcc_map PDBov:pdbx_dcc_map.auth_asym_id ?asym_id ; not water, not ion
PDBov:pdbx_dcc_map.auth_comp_id ?comp_id ;PDBov:pdbx_dcc_map.RSR ?RSR .

FILTER (xsd:float(?RSR) < 0.1)
} GROUP BY ?PDB_ID ?enzyme ?ligand ?comp_id✍ RSR < 0.1

Example2:Search wwPDB/RDF-validation
Found 15k pairs of enzyme-ligand complexes of which real space R-factor (RSR) of ligand is lessthan 10%.
PDB ID, enzyme name, ligand name, ligand (3-letters code), minimum RSR value of the ligand"4CK1","INTEGRASE","(4-CARBOXY-1,3-BENZODIOXOL-5-YL)METHYL-[[2-[(4METHOXYPHENYL)METHYLCARBAMOYL]PHENYL]METHYL]AZANIUM","OM1","0.081""2IOD","Dihydroflavonol 4-reductase","NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDEPHOSPHATE","NAP","0.091""5BYR","Iron hydrogenase 1","FE2/S2 (INORGANIC) CLUSTER","FES","0.096""2PU0","Enolase","PHOSPHONOACETOHYDROXAMIC ACID","PAH","0.075""4LV2","Beta-lactamase","[1-(6-chloropyrimidin-4-yl)-1H-pyrazol-4-yl]boronic acid","N95","0.083""3OLE","Pancreatic alpha-amylase","ALPHA-D-GLUCOSE","GLC","0.084""4MOR","Pyranose 2-oxidase","DODECAETHYLENE GLYCOL","12P","0.093""4FKX","Nucleoside diphosphate kinase","CYTIDINE-5'-DIPHOSPHATE","CDP","0.073""4JPU","Cytochrome c peroxidase","PROTOPORPHYRIN IX CONTAINING FE","HEM","0.094""1GTV","THYMIDYLATE KINASE","THYMIDINE-5'-DIPHOSPHATE","TYD","0.090""5IA2","7-(5-hydroxy-2-methylphenyl)-8-(2-methoxyphenyl)-1-methyl-1H-imidazo[2,1-f]purine2,4(3H,8H)-dione","7-(5-hydroxy-2-methylphenyl)-8-(2-methoxyphenyl)-1-methyl-1Himidazo[2,1-f]purine-2,4(3H,8H)-dione","L66","0.077""1NFQ","Putative oxidoreductase Rv2002","1,4-DIHYDRONICOTINAMIDE ADENINEDINUCLEOTIDE","NAI","0.090”

Example2:Search wwPDB/RDF-validation"4CK1","INTEGRASE","(4-CARBOXY-1,3-BENZODIOXOL-5-YL)METHYL-[[2-[(4METHOXYPHENYL)METHYLCARBAMOYL]PHENYL]METHYL]AZANIUM","OM1","0.081"19

Example2:Search wwPDB/RDF-validation“3OLE”,“Pancreatic alpha-amylase”,“ALPHA-D-GLUCOSE","GLC","0.084"20

Example3:Search wwPDB/RDF-validation
Search all enzyme-ligand complexes of which percentage of outlier in real space R-factor, definedby Z-score (RSRZ) is larger than 2, of enzyme is less than 1%. (showing only essential part of about
20 line-SPARQL query)
PREFIX PDBov: <https://rdf.wwpdb.org/schema/pdbx-validation-v1.owl#>
SELECT ?PDB_ID ?Enzyme (GROUP_CONCAT(?Ligand; SEPARATOR=",") AS ?Ligands)?RSRZ_outliers_percent
FROM <http://rdf.wwpdb.org/pdb-validation>
WHERE {
?map_overall PDBov:pdbx_dcc_map_overall.entry_id ?PDB_ID ;PDBov:pdbx_dcc_map_overall.RSRZ_outliers_percent ?RSRZ_outliers_percent .
FILTER (xsd:float(?RSRZ_outliers_percent) < 0.01)✍ % of outliers in RSRZ < 1%BIND (IRI(CONCAT("https://rdf.wwpdb.org/pdb-validation/", ?PDB_ID, "/entityCategory")) AS?entity_category)?entity_category PDBov:has_entity ?entity .
?entity PDBov:link_to_enzyme ?link_to_enzume ;PDBov:entity.pdbx_description ?Enzyme .

✍selection of enzyme…
}✍ligand selection (omission)Example3:Search wwPDB/RDF-validation
Found 5k pairs of enzyme-ligand complexes of which percentage of outlier in real space R-factor(RSRZ) of enzyme is less than 1%, 1k pairs for 0%.
PDB ID, enzyme name, ligand name, percentage of outliers in RSR value of the enzyme"1BUL","NMC-A BETA-LACTAMASE","2-(1-CARBOXY-2-HYDROXY-2-METHYL-PROPYL)5,5-DIMETHYL-THIAZOLIDINE-4-CARBOXYLIC ACID,2-(N-MORPHOLINO)ETHANESULFONIC ACID","0.00""5A1G","S-ADENOSYLMETHIONINE SYNTHASE ISOFORM TYPE2","(DIPHOSPHONO)AMINOPHOSPHONIC ACID,[(3S)-3-amino-3carboxypropyl]{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2yl]methyl}ethylsulfonium,(4S)-2-METHYL-2,4-PENTANEDIOL,IMIDAZOLE","0.00""2DRS","Xylanase Y","GLYCEROL","0.00""2AS1","Cytochrome c peroxidase, mitochondrial","PROTOPORPHYRIN IX CONTAINING
FE,THIOPHENE-3-CARBOXIMIDAMIDE","0.00""1H4W","TRYPSIN IVA","BENZAMIDINE","0.00""142L","T4 LYSOZYME","BETA-MERCAPTOETHANOL","0.00""4CIK","PLASMINOGEN","5-[(2R,4S)-2-(phenylmethyl)piperidin-4-yl]-1,2-oxazol-3-one","0.00""4L4O","Endo-1,4-beta-xylanase","TRIS-HYDROXYMETHYL-METHYL-AMMONIUM","0.00""4G5P","Epidermal growth factor receptor","N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)tetrahydrofuran-3-yloxy]quinazolin-6-yl}-4-(dimethylamino)butanamide","0.00""3GA6","Exodeoxyribonuclease","GLYCEROL","0.00"

終わりに・・
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If you want to do complicated queries,
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Acknowledgements24