Blundell group

Sir Professor Tom Blundell research group

Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats.

Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats.

Nature. 2009 Dec 20;

Authors: Sibanda BL, Chirgadze DY, Blundell TL

Broken chromosomes arising from DNA double-strand breaks result from endogenous events such as the production of reactive oxygen species during cellular metabolism, as well as from exogenous sources such as ionizing radiation. Left unrepaired or incorrectly repaired they can lead to genomic changes that may result in cell death or cancer. DNA-dependent protein kinase (DNA-PK), a holoenzyme that comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer Ku70/Ku80, has a major role in non-homologous end joining-the main pathway in mammals used to repair double-strand breaks. DNA-PKcs is a serine/threonine protein kinase comprising a single polypeptide chain of 4,128 amino acids and belonging to the phosphatidylinositol-3-OH kinase (PI(3)K)-related protein family. DNA-PKcs is involved in the sensing and transmission of DNA damage signals to proteins such as p53, setting off events that lead to cell cycle arrest. It phosphorylates a wide range of substrates in vitro, including Ku70/Ku80, which is translocated along DNA. Here we present the crystal structure of human DNA-PKcs at 6.6 A resolution, in which the overall fold is clearly visible, to our knowledge, for the first time. The many alpha-helical HEAT repeats (helix-turn-helix motifs) facilitate bending and allow the polypeptide chain to fold into a hollow circular structure. The carboxy-terminal kinase domain is located on top of this structure, and a small HEAT repeat domain that probably binds DNA is inside. The structure provides a flexible cradle to promote DNA double-strand-break repair.

PMID: 20023628 [PubMed - as supplied by publisher]

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Dr Dimitri (aka Dima) Y. Chirgadze
Senior Research Associate

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dyc21@cam.ac.uk

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Published structures

PDBStructureTitle
3N59Type II dehydroquinase from Mycobacterium Tuberculosis complexed with 3-dehydroshikimate
3N8KType II dehydroquinase from Mycobacterium tuberculosis complexed with citrazinic acid
3KVIStructural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - T42A mutant in complex with fluoro-acetate
3KVUStructural basis of the activity and substrate specificity of the fluoroacetyl-CoA FlK - T42S mutant in complex with Acetyl-CoA
3KVZStructural basis of the activity and substrate specificity of the fluoroacetyl-CoA thiesterase FlK - wild type FlK in complex with FAcCPan
3KW1Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA FlK - Wild type FlK in complex with FAcOPan
3KX8Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK
3KUVStructural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - T42S mutant in complex with acetate.
3KUWStructural basis of the activity ans substrate specificity of the fluoroacetyl-CoA thioesterase FlK - T42S mutant in complex with Fluoro-acetate
3KV7Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - wild type FlK in complex with acetate
3KV8Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - Wild type FlK in complex with fluoro-acetate
3KX7Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA FlK - apo wild type FlK
3LE8Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.70 Angstrom resolution in complex with 2-(2-((benzofuran-2-carboxamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid
2WVICRYSTAL STRUCTURE OF THE N-TERMINAL DOMAIN OF BUBR1
3HWOCrystal structure of Escherichia coli enterobactin-specific isochorismate synthase EntC in complex with isochorismate
3KGVCrystal Structure of Human DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs)
3ISJCrystal structure of pantothenate synthetase from Mycobacterium tuberculosis in complex with 5-methoxy-N-(methylsulfonyl)-1H-indole-2-carboxamide
3IMCCrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.6 Ang resolution in complex with fragment compound 5-methoxyindole, sulfate and glycerol
3IMECrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 2.40 Ang resolution in complex with fragment compound 1-Benzofuran-2-carboxylic acid
3IMGCrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.8 Ang resolution in a ternary complex with fragment compounds 5-methoxyindole and 1-benzofuran-2-carboxylic acid
3IUBCrystal structure of pantothenate synthetase from Mycobacterium tuberculosis in complex with 5-Methoxy-N-(5-methylpyridin-2-ylsulfonyl)-1H-indole-2-carboxamide
3IUECrystal structure of pantothenate synthetase in complex with 2-(5-methoxy-2-(5-Methylpyridin-2-ylsulfonylcarbamoyl)-1H-indol-1-yl) acetic acid
3IVCCrystal structure of pantothenate synthetase in complex with 2-(2-((benzofuran-2-ylmethoxy)carbonyl)-5-methoxy-1H-indol-1-yl)acetic acid
3IVGCrystal structure of pantothenate synthetase in complex with 2-(2-((benzofuran-2-sulfonamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid
3IVXCrystal structure of pantothenate synthetase in complex with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid
3G04Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody
3H4IChimeric Glycosyltransferase for the generation of novel natural products
3H4TChimeric Glycosyltransferase for the generation of novel natural products - GtfAH1 in complex with UDP-2F-Glc
3ESLCrystal structure of the conserved N-terminal domain of the mitotic checkpoint component BUB1
2K5XChemical shift structure of COLICIN E9 DNASE domain with its cognate immunity protein IM9
3COVCrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.5 Ang resolution- apo form
3COWCrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.8 Ang resolution- in complex with sulphonamide inhibitor 2
3COYCrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 2.05 Ang resolution- in complex with sulphonamide inhibitor 3
3COZCrystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 2.0 Ang resolution- in complex with sulphonamide inhibitor 4
3E4RCrystal structure of the alkanesulfonate binding protein (SsuA) from the phytopathogenic bacteria Xanthomonas axonopodis pv. citri bound to HEPES
3DARCrystal structure of D2 domain from human FGFR2
2QM4Crystal structure of human XLF/Cernunnos, a non-homologous end-joining factor
2PZJCrystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NAD+
2PZKCrystal structure of the Bordetella bronchiseptica enzyme WbmG in complex with NAD
2PZLCrystal structure of the Bordetella bronchiseptica enzyme WbmG in complex with NAD and UDP
2PZMCrystal structure of the Bordetella bronchiseptica enzyme WbmG in complex with NAD and UDP
2Q1SCrystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NADH
2Q1TCrystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NAD+ and UDP
2Q1UCrystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NAD+ and UDP
2Q1WCrystal structure of the Bordetella bronchiseptica enzyme WbmH in complex with NAD+
2OFPCrystal structure of Escherichia coli ketopantoate reductase in a ternary complex with NADP+ and pantoate
2J66STRUCTURAL CHARACTERISATION OF BTRK DECARBOXYLASE FROM BUTIROSIN BIOSYNTHESIS
2C7TCRYSTAL STRUCTURE OF THE PLP-BOUND FORM OF BTRR, A DUAL FUNCTIONAL AMINOTRANSFERASE INVOLVED IN BUTIROSIN BIOSYNTHESIS.
2C81CRYSTAL STRUCTURES OF THE PLP- AND PMP-BOUND FORMS OF BTRR, A DUAL FUNCTIONAL AMINOTRANSFERASE INVOLVED IN BUTIROSIN BIOSYNTHESIS.
2HE0Crystal structure of a human Notch1 ankyrin domain mutant
1YONEscherichia coli ketopantoate reductase in complex with 2-monophosphoadenosine-5'-diphosphate
1XESCrystal structure of stilbene synthase from Pinus sylvestris
1XETCrystal structure of stilbene synthase from Pinus sylvestris, complexed with methylmalonyl CoA
2FN0Crystal structure of Yersinia enterocolitica salicylate synthase (Irp9)
2FN1Crystal structures of Yersinia enterocolitica salicylate synthase (Irp9) in complex with the reaction products salicylate and pyruvate
1Z56Co-Crystal Structure of Lif1p-Lig4p
2ASUCrystal Structure of the beta-chain of HGFl/MSP
1TJ6Crystal structure of the Xenopus tropicalis Spred1 EVH-1 domain
1YYHCrystal structure of the human Notch 1 ankyrin domain
1YJQCrystal structure of ketopantoate reductase in complex with NADP+
1XODCrystal structure of X. tropicalis Spred1 EVH-1 domain
2BF9ANISOTROPIC REFINEMENT OF AVIAN (TURKEY) PANCREATIC POLYPEPTIDE AT 0.99 ANGSTROMS RESOLUTION.
1RQFStructure of CK2 beta subunit crystallized in the presence of a p21WAF1 peptide
1PWACrystal structure of Fibroblast Growth Factor 19
1PPYNative precursor of pyruvoyl dependent Aspartate decarboxylase
1PQES25A mutant of pyruvoyl dependent aspartate decarboxylase
1PQFGlycine 24 to Serine mutation of aspartate decarboxylase
1PQHSerine 25 to Threonine mutation of aspartate decarboxylase
1PYQUnprocessed Aspartate Decarboxylase Mutant, with Alanine inserted at position 24
1PYUProcessed Aspartate Decarboxylase Mutant with Ser25 mutated to Cys
1PT0Unprocessed Pyruvoyl Dependent Aspartate Decarboxylase with an Alanine insertion at position 26
1PT1Unprocessed Pyruvoyl Dependent Aspartate Decarboxylase with Histidine 11 Mutated to Alanine
1URFHR1B DOMAIN FROM PRK1
1PZNRad51 (RadA)
1M3UCrystal Structure of Ketopantoate Hydroxymethyltransferase complexed the Product Ketopantoate
1QIACRYSTAL STRUCTURE OF STROMELYSIN CATALYTIC DOMAIN
1QICCRYSTAL STRUCTURE OF STROMELYSIN CATALYTIC DOMAIN
1N0WCrystal structure of a RAD51-BRCA2 BRC repeat complex
1KS9Ketopantoate Reductase from Escherichia coli
1IK9CRYSTAL STRUCTURE OF A XRCC4-DNA LIGASE IV COMPLEX
1GP9A NEW CRYSTAL FORM OF THE NK1 SPLICE VARIANT OF HGF/SF DEMONSTRATES EXTENSIVE HINGE MOVEMENT AND SUGGESTS THAT THE NK1 DIMER ORIGINATES BY DOMAIN SWAPPING
1K9YThe PAPase Hal2p complexed with magnesium ions and reaction products: AMP and inorganic phosphate
1K9ZThe PAPase Hal2p complexed with zinc ions
1KA0The PAPase Hal2p complexed with a sodium ion and the reaction product AMP
1KA1The PAPase Hal2p complexed with calcium and magnesium ions and reaction substrate: PAP
1GMNCRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR
1GMOCRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR
1JP4Crystal Structure of an Enzyme Displaying both Inositol-Polyphosphate 1-Phosphatase and 3'-Phosphoadenosine-5'-Phosphate Phosphatase Activities
1IHOCRYSTAL APO-STRUCTURE OF PANTOTHENATE SYNTHETASE FROM E. COLI
1E0OCRYSTAL STRUCTURE OF A TERNARY FGF1-FGFR2-HEPARIN COMPLEX
1QGXX-RAY STRUCTURE OF YEAST HAL2P
1QIBCRYSTAL STRUCTURE OF GELATINASE A CATALYTIC DOMAIN
1CIZX-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXES WITH NON-PEPTIDE INHIBITORS: IMPLICATION FOR INHIBITOR SELECTIVITY
1B8YX-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXED WITH NON-PEPTIDE INHIBITORS: IMPLICATIONS FOR INHIBITOR SELECTIVITY
1CAQX-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXES WITH NON-PEPTIDE INHIBITORS: IMPLICATION FOR INHIBITOR SELECTIVITY
1BLXP19INK4D/CDK6 COMPLEX
1JOHTHE STRUCTURE OF ANTIAMOEBIN I, A MEMBRANE-ACTIVE PEPTIDE
1NK1NK1 FRAGMENT OF HUMAN HEPATOCYTE GROWTH FACTOR/SCATTER FACTOR (HGF/SF) AT 2.5 ANGSTROM RESOLUTION
1SGFCRYSTAL STRUCTURE OF 7S NGF: A COMPLEX OF NERVE GROWTH FACTOR WITH FOUR BINDING PROTEINS (SERINE PROTEINASES)
1AW8PYRUVOYL DEPENDENT ASPARTATE DECARBOXYLASE
2JXRSTRUCTURE OF YEAST PROTEINASE A
1CZICHYMOSIN COMPLEX WITH THE INHIBITOR CP-113972
1EPODIRECT OBSERVATION BY X-RAY ANALYSIS OF THE TETRAHEDRAL ""INTERMEDIATE"" OF ASPARTIC PROTEINASES
1BETNEW PROTEIN FOLD REVEALED BY A 2.3 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF NERVE GROWTH FACTOR
1SACTHE STRUCTURE OF PENTAMERIC HUMAN SERUM AMYLOID P COMPONENT
1BBSX-RAY ANALYSES OF PEPTIDE INHIBITOR COMPLEXES DEFINE THE STRUCTURAL BASIS OF SPECIFICITY FOR HUMAN AND MOUSE RENINS
1EEDX-RAY CRYSTALLOGRAPHIC ANALYSIS OF INHIBITION OF ENDOTHIAPEPSIN BY CYCLOHEXYL RENIN INHIBITORS
1ENTX-RAY ANALYSES OF ASPARTIC PROTEINASES. THE THREE-DIMENSIONAL STRUCTURE AT 2.1 ANGSTROMS RESOLUTION OF ENDOTHIAPEPSIN
1SMRTHE 3-D STRUCTURE OF MOUSE SUBMAXILLARY RENIN COMPLEXED WITH A DECAPEPTIDE INHIBITOR CH-66 BASED ON THE 4-16 FRAGMENT OF RAT ANGIOTENSINOGEN
1MPPX-RAY ANALYSES OF ASPARTIC PROTEINASES. V. STRUCTURE AND REFINEMENT AT 2.0 ANGSTROMS RESOLUTION OF THE ASPARTIC PROTEINASE FROM MUCOR PUSILLUS
1PDASTRUCTURE OF PORPHOBILINOGEN DEAMINASE REVEALS A FLEXIBLE MULTIDOMAIN POLYMERASE WITH A SINGLE CATALYTIC SITE
2BB2X-RAY ANALYSIS OF BETA B2-CRYSTALLIN AND EVOLUTION OF OLIGOMERIC LENS PROTEINS
4GCRSTRUCTURE OF THE BOVINE EYE LENS PROTEIN GAMMA-B (GAMMA-II)-CRYSTALLIN AT 1.47 ANGSTROMS
4CMSX-RAY ANALYSES OF ASPARTIC PROTEINASES IV. STRUCTURE AND REFINEMENT AT 2.2 ANGSTROMS RESOLUTION OF BOVINE CHYMOSIN
3ER5THE ACTIVE SITE OF ASPARTIC PROTEINASES
4ER4HIGH-RESOLUTION X-RAY ANALYSES OF RENIN INHIBITOR-ASPARTIC PROTEINASE COMPLEXES
5ER2HIGH-RESOLUTION X-RAY DIFFRACTION STUDY OF THE COMPLEX BETWEEN ENDOTHIAPEPSIN AND AN OLIGOPEPTIDE INHIBITOR. THE ANALYSIS OF THE INHIBITOR BINDING AND DESCRIPTION OF THE RIGID BODY SHIFT IN THE ENZYME
2ER0X-RAY STUDIES OF ASPARTIC PROTEINASE-STATINE INHIBITOR COMPLEXES
2ER7X-RAY ANALYSES OF ASPARTIC PROTEINASES.III. THREE-DIMENSIONAL STRUCTURE OF ENDOTHIAPEPSIN COMPLEXED WITH A TRANSITION-STATE ISOSTERE INHIBITOR OF RENIN AT 1.6 ANGSTROMS RESOLUTION
2ER9X-RAY STUDIES OF ASPARTIC PROTEINASE-STATINE INHIBITOR COMPLEXES.
5ER1A rational approach to the design of antihypertensives. x-ray studies of complexes between ASPARTIC PROTEINASES and AMINOALCOHOL RENIN INHIBITORS
5PEPX-RAY ANALYSES OF ASPARTIC PROTEASES. II. THREE-DIMENSIONAL STRUCTURE OF THE HEXAGONAL CRYSTAL FORM OF PORCINE PEPSIN AT 2.3 ANGSTROMS RESOLUTION
4INSTHE STRUCTURE OF 2ZN PIG INSULIN CRYSTALS AT 1.5 ANGSTROMS RESOLUTION
1XY1CRYSTAL STRUCTURE ANALYSIS OF DEAMINO-OXYTOCIN. CONFORMATIONAL FLEXIBILITY AND RECEPTOR BINDING
1XY2CRYSTAL STRUCTURE ANALYSIS OF DEAMINO-OXYTOCIN. CONFORMATIONAL FLEXIBILITY AND RECEPTOR BINDING
1PPTX-RAY ANALYSIS (1.4-ANGSTROMS RESOLUTION) OF AVIAN PANCREATIC POLYPEPTIDE. SMALL GLOBULAR PROTEIN HORMONE

H Leonardo Silvestre

My research is in fragment-based drug discovery.
I am applying this technique to develop new inhibitors of Pantotheante Synthetase, a known target against Mycobacterium tuberculosis.

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I am post doctoral fellow in Biochemistry in the Tom Blundell Research group. I am interested in drug discovery and natural products biosynthesis.

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