New light for science: synchrotron radiation in structural medicine.

Macromolecular crystallography (MX) is a powerful method for obtaining detailed three-dimensional structural information about macromolecules. MX using synchrotron X-rays has contributed, significantly, to both fundamental and applied research, including the structure-based design of drugs to combat important diseases. New third-generation synchrotrons offer substantial improvements in terms of quality and brightness of the X-ray beams they produce. Important classes of macromolecules, such as membrane proteins (including many receptors) and macromolecular complexes, are difficult to obtain in quantity and to crystallise, which has hampered analysis by MX. Intensely bright X-rays from the latest synchrotrons will enable the use of extremely small crystals, and should usher in a period of rapid progress in resolving these previously refractory structures.

[1]  C. Sawyers.  Chronic myeloid leukemia. , 1999, The New England journal of medicine.

[2]  G. Superti-Furga,et al.  Structural Basis for the Autoinhibition of c-Abl Tyrosine Kinase , 2003, Cell.

[3]  Edward N Baker,et al.  The potential impact of structural genomics on tuberculosis drug discovery. , 2006, Drug discovery today.

[4]  Stephen K Burley,et al.  A Novel Mode of Gleevec Binding Is Revealed by the Structure of Spleen Tyrosine Kinase* , 2004, Journal of Biological Chemistry.

[5]  B. Druker,et al.  Oncogenes and Tumor Suppressors (795 articles) , 2004 .

[6]  B. Druker,et al.  Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy , 2002, Leukemia.

[7]  Olof Svensson,et al.  Automation of macromolecular crystallography beamlines. , 2005, Progress in biophysics and molecular biology.

[8]  J. Kuriyan,et al.  Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. , 2002, Cancer cell.

[9]  J. Mestan,et al.  Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. , 2005, Biochimica et biophysica acta.

[10]  Christian Riekel,et al.  Recent developments in microdiffraction on protein crystals , 2004 .

[11]  O. Witte,et al.  The BCR-ABL story: bench to bedside and back. , 2004, Annual review of immunology.

[12]  James C Sacchettini,et al.  Crystal Structures of Mycolic Acid Cyclopropane Synthases fromMycobacterium tuberculosis * , 2002, The Journal of Biological Chemistry.

[13]  E. Garman,et al.  Controlling influenza by inhibiting the virus's neuraminidase. , 2004, Current drug targets.

[14]  Jeremy L. Praissman,et al.  Life in the fast lane for protein crystallization and X-ray crystallography. , 2005, Progress in biophysics and molecular biology.

[15]  C. Nave,et al.  Radiation damage in protein crystals at low temperature. , 1994, Acta crystallographica. Section D, Biological crystallography.

[16]  K. Lundstrom.  Structural genomics of GPCRs. , 2005, Trends in biotechnology.

[17]  F. Schotte,et al.  Picosecond time-resolved X-ray crystallography: probing protein function in real time. , 2004, Journal of structural biology.

[18]  So Iwata,et al.  Methods and Results in Crystallization of Membrane Proteins , 2003 .

[19]  Atique U. Ahmed,et al.  Mutator phenotype of BCR – ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase β , 1999, Oncogene.

[20]  C. Sawyers,et al.  Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G. Daley,et al.  Mechanisms of Autoinhibition and STI-571/Imatinib Resistance Revealed by Mutagenesis of BCR-ABL , 2003, Cell.

[22]  B. Chait,et al.  The structure of the potassium channel: molecular basis of K+ conduction and selectivity. , 1998, Science.

[23]  F Cipriani,et al.  Protein microcrystals and the design of a microdiffractometer: current experience and plans at EMBL and ESRF/ID13. , 1999, Acta crystallographica. Section D, Biological crystallography.

[24]  Robert A. Grothe,et al.  Structure of the cross-β spine of amyloid-like fibrils , 2005, Nature.

[25]  F. Lee,et al.  Dasatinib (BMS-354825) Overcomes Multiple Mechanisms of Imatinib Resistance in Chronic Myeloid Leukemia (CML). , 2005 .

[26]  N R Taylor,et al.  Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B. , 1998, Journal of medicinal chemistry.

[27]  Manfred Burghammer,et al.  Small is beautiful: protein micro-crystallography , 1998, Nature Structural Biology.

[28]  J. Mestan,et al.  Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. , 2004, Mini reviews in medicinal chemistry.

[29]  Manfred Burghammer,et al.  Protein crystallography microdiffraction. , 2005, Current opinion in structural biology.

[30]  F. Schluenzen,et al.  Structure of Functionally Activated Small Ribosomal Subunit , 2000 .

[31]  Christopher Dye,et al.  The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. , 2003, Archives of internal medicine.

[32]  F. Schluenzen,et al.  Structure of Functionally Activated Small Ribosomal Subunit at 3.3 Å Resolution , 2000, Cell.

[33]  Poul Nissen,et al.  Phosphoryl Transfer and Calcium Ion Occlusion in the Calcium Pump , 2004, Science.

[34]  R. Gottlob,et al.  Methods and Results , 1986 .

[35]  Gerhard Hummer,et al.  Unveiling functional protein motions with picosecond x-ray crystallography and molecular dynamics simulations. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Roderick E. Hubbard,et al.  Structure-based drug discovery : an overview , 2006 .

[37]  James C. Sacchettini,et al.  Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase , 2000, Nature.

[38]  T. Steitz,et al.  The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. , 2000, Science.

[39]  R. Larson,et al.  Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. , 2002, Blood.

[40]  K. Moffat,et al.  Radiation damage of protein crystals at cryogenic temperatures between 40 K and 150 K. , 2002, Journal of synchrotron radiation.

[41]  Ana González,et al.  Optimizing data collection for structure determination. , 2003, Acta crystallographica. Section D, Biological crystallography.

[42]  F. R. Elder,et al.  Radiation from Electrons in a Synchrotron , 1947 .

[43]  John Kuriyan,et al.  Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). , 2001, Cancer research.

[44]  P. Seeburg,et al.  Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. , 2000, Science.

[45]  Vivek Sharma,et al.  TB drug discovery: addressing issues of persistence and resistance. , 2004, Tuberculosis.

[46]  W. Hendrickson.  Determination of macromolecular structures from anomalous diffraction of synchrotron radiation. , 1991, Science.

[47]  K. Holmes,et al.  Synchrotron Radiation as a Source for X-ray Diffraction , 1971, Nature.

[48]  Gyorgy Snell,et al.  Automated sample mounting and alignment system for biological crystallography at a synchrotron source. , 2004, Structure.

[49]  Eric Gouaux,et al.  Fluorescence-detection size-exclusion chromatography for precrystallization screening of integral membrane proteins. , 2006, Structure.

[50]  S. Vasavanonda,et al.  ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[51]  C. Vonrhein,et al.  Structure of the 30S ribosomal subunit , 2000, Nature.

[52]  B. Druker,et al.  Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. , 2003, Blood.

[53]  Elspeth F Garman,et al.  Experimental determination of the radiation dose limit for cryocooled protein crystals. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[54]  S. Christensen,et al.  Natural products as starting materials for development of second-generation SERCA inhibitors targeted towards prostate cancer cells. , 2006, Bioorganic & medicinal chemistry.

[55]  D. Stammers,et al.  HIV reverse transcriptase structures: designing new inhibitors and understanding mechanisms of drug resistance. , 2005, Trends in pharmacological sciences.

[56]  L. Johnson,et al.  Protein Kinase Inhibitors: Insights into Drug Design from Structure , 2004, Science.

[57]  D. Tomboulian,et al.  Spectral and Angular Distribution of Ultraviolet Radiation from the 300-Mev Cornell Synchrotron , 1956 .

[58]  James C Sacchettini,et al.  Biochemical and Structural Studies of Malate Synthase fromMycobacterium tuberculosis * , 2002, The Journal of Biological Chemistry.

[59]  H. Kantarjian,et al.  Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. , 2003, Blood.

[60]  Christopher Dye,et al.  Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. , 2005, JAMA.

[61]  C. Nicolini,et al.  Structure and growth of ultrasmall protein microcrystals by synchrotron radiation: I. µGISAXS and µdiffraction of P450scc , 2006 .

[62]  J. Melo,et al.  The molecular biology of chronic myeloid leukemia. , 2000, Blood.

[63]  C. Sawyers,et al.  Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. , 2001, The New England journal of medicine.

[64]  T. Earnest,et al.  Crystal Structure of the Ribosome at 5.5 Å Resolution , 2001, Science.

[65]  Daniel K. Treiber,et al.  Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. , 2006, Cancer research.

[66]  J L Sussman,et al.  Specific chemical and structural damage to proteins produced by synchrotron radiation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[68]  Ehmke Pohl,et al.  Automation of the EMBL Hamburg protein crystallography beamline BW7B. , 2004, Journal of synchrotron radiation.

[69]  A Wlodawer,et al.  Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. , 1998, Annual review of biophysics and biomolecular structure.