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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]
Dr Dimitri (aka Dima) Y. Chirgadze
Senior Research Associate
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dyc21@cam.ac.uk
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| PDB | Structure | Title |
|---|---|---|
| 3N59 | ![]() | Type II dehydroquinase from Mycobacterium Tuberculosis complexed with 3-dehydroshikimate |
| 3N8K | ![]() | Type II dehydroquinase from Mycobacterium tuberculosis complexed with citrazinic acid |
| 3KVI | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - T42A mutant in complex with fluoro-acetate |
| 3KVU | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA FlK - T42S mutant in complex with Acetyl-CoA |
| 3KVZ | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thiesterase FlK - wild type FlK in complex with FAcCPan |
| 3KW1 | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA FlK - Wild type FlK in complex with FAcOPan |
| 3KX8 | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK |
| 3KUV | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - T42S mutant in complex with acetate. |
| 3KUW | ![]() | Structural basis of the activity ans substrate specificity of the fluoroacetyl-CoA thioesterase FlK - T42S mutant in complex with Fluoro-acetate |
| 3KV7 | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - wild type FlK in complex with acetate |
| 3KV8 | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA thioesterase FlK - Wild type FlK in complex with fluoro-acetate |
| 3KX7 | ![]() | Structural basis of the activity and substrate specificity of the fluoroacetyl-CoA FlK - apo wild type FlK |
| 3LE8 | ![]() | Crystal 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 |
| 2WVI | ![]() | CRYSTAL STRUCTURE OF THE N-TERMINAL DOMAIN OF BUBR1 |
| 3HWO | ![]() | Crystal structure of Escherichia coli enterobactin-specific isochorismate synthase EntC in complex with isochorismate |
| 3KGV | ![]() | Crystal Structure of Human DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs) |
| 3ISJ | ![]() | Crystal structure of pantothenate synthetase from Mycobacterium tuberculosis in complex with 5-methoxy-N-(methylsulfonyl)-1H-indole-2-carboxamide |
| 3IMC | ![]() | Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.6 Ang resolution in complex with fragment compound 5-methoxyindole, sulfate and glycerol |
| 3IME | ![]() | Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 2.40 Ang resolution in complex with fragment compound 1-Benzofuran-2-carboxylic acid |
| 3IMG | ![]() | Crystal 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 |
| 3IUB | ![]() | Crystal structure of pantothenate synthetase from Mycobacterium tuberculosis in complex with 5-Methoxy-N-(5-methylpyridin-2-ylsulfonyl)-1H-indole-2-carboxamide |
| 3IUE | ![]() | Crystal structure of pantothenate synthetase in complex with 2-(5-methoxy-2-(5-Methylpyridin-2-ylsulfonylcarbamoyl)-1H-indol-1-yl) acetic acid |
| 3IVC | ![]() | Crystal structure of pantothenate synthetase in complex with 2-(2-((benzofuran-2-ylmethoxy)carbonyl)-5-methoxy-1H-indol-1-yl)acetic acid |
| 3IVG | ![]() | Crystal structure of pantothenate synthetase in complex with 2-(2-((benzofuran-2-sulfonamido)methyl)-5-methoxy-1H-indol-1-yl)acetic acid |
| 3IVX | ![]() | Crystal structure of pantothenate synthetase in complex with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid |
| 3G04 | ![]() | Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody |
| 3H4I | ![]() | Chimeric Glycosyltransferase for the generation of novel natural products |
| 3H4T | ![]() | Chimeric Glycosyltransferase for the generation of novel natural products - GtfAH1 in complex with UDP-2F-Glc |
| 3ESL | ![]() | Crystal structure of the conserved N-terminal domain of the mitotic checkpoint component BUB1 |
| 2K5X | ![]() | Chemical shift structure of COLICIN E9 DNASE domain with its cognate immunity protein IM9 |
| 3COV | ![]() | Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.5 Ang resolution- apo form |
| 3COW | ![]() | Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.8 Ang resolution- in complex with sulphonamide inhibitor 2 |
| 3COY | ![]() | Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 2.05 Ang resolution- in complex with sulphonamide inhibitor 3 |
| 3COZ | ![]() | Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 2.0 Ang resolution- in complex with sulphonamide inhibitor 4 |
| 3E4R | ![]() | Crystal structure of the alkanesulfonate binding protein (SsuA) from the phytopathogenic bacteria Xanthomonas axonopodis pv. citri bound to HEPES |
| 3DAR | ![]() | Crystal structure of D2 domain from human FGFR2 |
| 2QM4 | ![]() | Crystal structure of human XLF/Cernunnos, a non-homologous end-joining factor |
| 2PZJ | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NAD+ |
| 2PZK | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmG in complex with NAD |
| 2PZL | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmG in complex with NAD and UDP |
| 2PZM | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmG in complex with NAD and UDP |
| 2Q1S | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NADH |
| 2Q1T | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NAD+ and UDP |
| 2Q1U | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmF in complex with NAD+ and UDP |
| 2Q1W | ![]() | Crystal structure of the Bordetella bronchiseptica enzyme WbmH in complex with NAD+ |
| 2OFP | ![]() | Crystal structure of Escherichia coli ketopantoate reductase in a ternary complex with NADP+ and pantoate |
| 2J66 | ![]() | STRUCTURAL CHARACTERISATION OF BTRK DECARBOXYLASE FROM BUTIROSIN BIOSYNTHESIS |
| 2C7T | ![]() | CRYSTAL STRUCTURE OF THE PLP-BOUND FORM OF BTRR, A DUAL FUNCTIONAL AMINOTRANSFERASE INVOLVED IN BUTIROSIN BIOSYNTHESIS. |
| 2C81 | ![]() | CRYSTAL STRUCTURES OF THE PLP- AND PMP-BOUND FORMS OF BTRR, A DUAL FUNCTIONAL AMINOTRANSFERASE INVOLVED IN BUTIROSIN BIOSYNTHESIS. |
| 2HE0 | ![]() | Crystal structure of a human Notch1 ankyrin domain mutant |
| 1YON | ![]() | Escherichia coli ketopantoate reductase in complex with 2-monophosphoadenosine-5'-diphosphate |
| 1XES | ![]() | Crystal structure of stilbene synthase from Pinus sylvestris |
| 1XET | ![]() | Crystal structure of stilbene synthase from Pinus sylvestris, complexed with methylmalonyl CoA |
| 2FN0 | ![]() | Crystal structure of Yersinia enterocolitica salicylate synthase (Irp9) |
| 2FN1 | ![]() | Crystal structures of Yersinia enterocolitica salicylate synthase (Irp9) in complex with the reaction products salicylate and pyruvate |
| 1Z56 | ![]() | Co-Crystal Structure of Lif1p-Lig4p |
| 2ASU | ![]() | Crystal Structure of the beta-chain of HGFl/MSP |
| 1TJ6 | ![]() | Crystal structure of the Xenopus tropicalis Spred1 EVH-1 domain |
| 1YYH | ![]() | Crystal structure of the human Notch 1 ankyrin domain |
| 1YJQ | ![]() | Crystal structure of ketopantoate reductase in complex with NADP+ |
| 1XOD | ![]() | Crystal structure of X. tropicalis Spred1 EVH-1 domain |
| 2BF9 | ![]() | ANISOTROPIC REFINEMENT OF AVIAN (TURKEY) PANCREATIC POLYPEPTIDE AT 0.99 ANGSTROMS RESOLUTION. |
| 1RQF | ![]() | Structure of CK2 beta subunit crystallized in the presence of a p21WAF1 peptide |
| 1PWA | ![]() | Crystal structure of Fibroblast Growth Factor 19 |
| 1PPY | ![]() | Native precursor of pyruvoyl dependent Aspartate decarboxylase |
| 1PQE | ![]() | S25A mutant of pyruvoyl dependent aspartate decarboxylase |
| 1PQF | ![]() | Glycine 24 to Serine mutation of aspartate decarboxylase |
| 1PQH | ![]() | Serine 25 to Threonine mutation of aspartate decarboxylase |
| 1PYQ | ![]() | Unprocessed Aspartate Decarboxylase Mutant, with Alanine inserted at position 24 |
| 1PYU | ![]() | Processed Aspartate Decarboxylase Mutant with Ser25 mutated to Cys |
| 1PT0 | ![]() | Unprocessed Pyruvoyl Dependent Aspartate Decarboxylase with an Alanine insertion at position 26 |
| 1PT1 | ![]() | Unprocessed Pyruvoyl Dependent Aspartate Decarboxylase with Histidine 11 Mutated to Alanine |
| 1URF | ![]() | HR1B DOMAIN FROM PRK1 |
| 1PZN | ![]() | Rad51 (RadA) |
| 1M3U | ![]() | Crystal Structure of Ketopantoate Hydroxymethyltransferase complexed the Product Ketopantoate |
| 1QIA | ![]() | CRYSTAL STRUCTURE OF STROMELYSIN CATALYTIC DOMAIN |
| 1QIC | ![]() | CRYSTAL STRUCTURE OF STROMELYSIN CATALYTIC DOMAIN |
| 1N0W | ![]() | Crystal structure of a RAD51-BRCA2 BRC repeat complex |
| 1KS9 | ![]() | Ketopantoate Reductase from Escherichia coli |
| 1IK9 | ![]() | CRYSTAL STRUCTURE OF A XRCC4-DNA LIGASE IV COMPLEX |
| 1GP9 | ![]() | A 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 |
| 1K9Y | ![]() | The PAPase Hal2p complexed with magnesium ions and reaction products: AMP and inorganic phosphate |
| 1K9Z | ![]() | The PAPase Hal2p complexed with zinc ions |
| 1KA0 | ![]() | The PAPase Hal2p complexed with a sodium ion and the reaction product AMP |
| 1KA1 | ![]() | The PAPase Hal2p complexed with calcium and magnesium ions and reaction substrate: PAP |
| 1GMN | ![]() | CRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR |
| 1GMO | ![]() | CRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR |
| 1JP4 | ![]() | Crystal Structure of an Enzyme Displaying both Inositol-Polyphosphate 1-Phosphatase and 3'-Phosphoadenosine-5'-Phosphate Phosphatase Activities |
| 1IHO | ![]() | CRYSTAL APO-STRUCTURE OF PANTOTHENATE SYNTHETASE FROM E. COLI |
| 1E0O | ![]() | CRYSTAL STRUCTURE OF A TERNARY FGF1-FGFR2-HEPARIN COMPLEX |
| 1QGX | ![]() | X-RAY STRUCTURE OF YEAST HAL2P |
| 1QIB | ![]() | CRYSTAL STRUCTURE OF GELATINASE A CATALYTIC DOMAIN |
| 1CIZ | ![]() | X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXES WITH NON-PEPTIDE INHIBITORS: IMPLICATION FOR INHIBITOR SELECTIVITY |
| 1B8Y | ![]() | X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXED WITH NON-PEPTIDE INHIBITORS: IMPLICATIONS FOR INHIBITOR SELECTIVITY |
| 1CAQ | ![]() | X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXES WITH NON-PEPTIDE INHIBITORS: IMPLICATION FOR INHIBITOR SELECTIVITY |
| 1BLX | ![]() | P19INK4D/CDK6 COMPLEX |
| 1JOH | ![]() | THE STRUCTURE OF ANTIAMOEBIN I, A MEMBRANE-ACTIVE PEPTIDE |
| 1NK1 | ![]() | NK1 FRAGMENT OF HUMAN HEPATOCYTE GROWTH FACTOR/SCATTER FACTOR (HGF/SF) AT 2.5 ANGSTROM RESOLUTION |
| 1SGF | ![]() | CRYSTAL STRUCTURE OF 7S NGF: A COMPLEX OF NERVE GROWTH FACTOR WITH FOUR BINDING PROTEINS (SERINE PROTEINASES) |
| 1AW8 | ![]() | PYRUVOYL DEPENDENT ASPARTATE DECARBOXYLASE |
| 2JXR | ![]() | STRUCTURE OF YEAST PROTEINASE A |
| 1CZI | ![]() | CHYMOSIN COMPLEX WITH THE INHIBITOR CP-113972 |
| 1EPO | ![]() | DIRECT OBSERVATION BY X-RAY ANALYSIS OF THE TETRAHEDRAL ""INTERMEDIATE"" OF ASPARTIC PROTEINASES |
| 1BET | ![]() | NEW PROTEIN FOLD REVEALED BY A 2.3 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF NERVE GROWTH FACTOR |
| 1SAC | ![]() | THE STRUCTURE OF PENTAMERIC HUMAN SERUM AMYLOID P COMPONENT |
| 1BBS | ![]() | X-RAY ANALYSES OF PEPTIDE INHIBITOR COMPLEXES DEFINE THE STRUCTURAL BASIS OF SPECIFICITY FOR HUMAN AND MOUSE RENINS |
| 1EED | ![]() | X-RAY CRYSTALLOGRAPHIC ANALYSIS OF INHIBITION OF ENDOTHIAPEPSIN BY CYCLOHEXYL RENIN INHIBITORS |
| 1ENT | ![]() | X-RAY ANALYSES OF ASPARTIC PROTEINASES. THE THREE-DIMENSIONAL STRUCTURE AT 2.1 ANGSTROMS RESOLUTION OF ENDOTHIAPEPSIN |
| 1SMR | ![]() | THE 3-D STRUCTURE OF MOUSE SUBMAXILLARY RENIN COMPLEXED WITH A DECAPEPTIDE INHIBITOR CH-66 BASED ON THE 4-16 FRAGMENT OF RAT ANGIOTENSINOGEN |
| 1MPP | ![]() | X-RAY ANALYSES OF ASPARTIC PROTEINASES. V. STRUCTURE AND REFINEMENT AT 2.0 ANGSTROMS RESOLUTION OF THE ASPARTIC PROTEINASE FROM MUCOR PUSILLUS |
| 1PDA | ![]() | STRUCTURE OF PORPHOBILINOGEN DEAMINASE REVEALS A FLEXIBLE MULTIDOMAIN POLYMERASE WITH A SINGLE CATALYTIC SITE |
| 2BB2 | ![]() | X-RAY ANALYSIS OF BETA B2-CRYSTALLIN AND EVOLUTION OF OLIGOMERIC LENS PROTEINS |
| 4GCR | ![]() | STRUCTURE OF THE BOVINE EYE LENS PROTEIN GAMMA-B (GAMMA-II)-CRYSTALLIN AT 1.47 ANGSTROMS |
| 4CMS | ![]() | X-RAY ANALYSES OF ASPARTIC PROTEINASES IV. STRUCTURE AND REFINEMENT AT 2.2 ANGSTROMS RESOLUTION OF BOVINE CHYMOSIN |
| 3ER5 | ![]() | THE ACTIVE SITE OF ASPARTIC PROTEINASES |
| 4ER4 | ![]() | HIGH-RESOLUTION X-RAY ANALYSES OF RENIN INHIBITOR-ASPARTIC PROTEINASE COMPLEXES |
| 5ER2 | ![]() | HIGH-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 |
| 2ER0 | ![]() | X-RAY STUDIES OF ASPARTIC PROTEINASE-STATINE INHIBITOR COMPLEXES |
| 2ER7 | ![]() | X-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 |
| 2ER9 | ![]() | X-RAY STUDIES OF ASPARTIC PROTEINASE-STATINE INHIBITOR COMPLEXES. |
| 5ER1 | ![]() | A rational approach to the design of antihypertensives. x-ray studies of complexes between ASPARTIC PROTEINASES and AMINOALCOHOL RENIN INHIBITORS |
| 5PEP | ![]() | X-RAY ANALYSES OF ASPARTIC PROTEASES. II. THREE-DIMENSIONAL STRUCTURE OF THE HEXAGONAL CRYSTAL FORM OF PORCINE PEPSIN AT 2.3 ANGSTROMS RESOLUTION |
| 4INS | ![]() | THE STRUCTURE OF 2ZN PIG INSULIN CRYSTALS AT 1.5 ANGSTROMS RESOLUTION |
| 1XY1 | ![]() | CRYSTAL STRUCTURE ANALYSIS OF DEAMINO-OXYTOCIN. CONFORMATIONAL FLEXIBILITY AND RECEPTOR BINDING |
| 1XY2 | ![]() | CRYSTAL STRUCTURE ANALYSIS OF DEAMINO-OXYTOCIN. CONFORMATIONAL FLEXIBILITY AND RECEPTOR BINDING |
| 1PPT | ![]() | X-RAY ANALYSIS (1.4-ANGSTROMS RESOLUTION) OF AVIAN PANCREATIC POLYPEPTIDE. SMALL GLOBULAR PROTEIN HORMONE |
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.
I am post doctoral fellow in Biochemistry in the Tom Blundell Research group. I am interested in drug discovery and natural products biosynthesis.