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A cell is an organization of millions of molecules

Structural Biology Medicine and Biology at the Atomic Scale. Organ  Tissue  Cell  Molecule  Atoms. A cell is an organization of millions of molecules Proper communication between these molecules is essential to the normal functioning of the cell

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A cell is an organization of millions of molecules

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  1. Structural Biology Medicine and Biology at the Atomic Scale Organ  Tissue  Cell  Molecule  Atoms • A cell is an organization of millions of molecules • Proper communication between these molecules is essential to the normal functioning of the cell • To understand communication between molecules:*determine the arrangement of the atoms*

  2. High Resolution Structural Biology Using atomic structure to understand how biomolecules communicate

  3. Anti-tumor Activity Duocarmycin SA The Reward: UnderstandingControl Atomic interactions Shape

  4. NER RPA BER RR Hierarchy of Structural Biology

  5. High Resolution Structural BiologyThree Complementary Techniques NMR Spectroscopy X-ray Crystallography Computation Determine experimentally or model 3D structures of biomolecules

  6. Biophysical Analysis RPA-A RPA-B Fluorescence Intensity RPA-AB Ratio of T-ag/RPA Computation What Tools Do We Use? Crystallography Expression/Mutations NMR

  7. X-ray NMR RF Signals Diffraction Pattern X-rays RF H0 • Direct detection of atom positions • Crystals • Indirect detection of H-H distances • In solution Experimental Determination of 3D Structures

  8. Representations of StructureConformational Ensemble Neither crystal nor solution structures are properly represented by a single conformation • Intrinsic motions • Imperfect data PRECISION RMSD of the ensemble

  9. Computational Determination of 3D Structures • Specify the forces that act on each atom • Simulate these forces on a molecule of known atomic composition • Start with experimental data or approximate experimental structure or just sequence • Many algorithms in use, all treatments for bio-macromolecules are empirical

  10. Unique Contributions of Each Structural Biology Technique • X-ray- highest resolution, automation coming • NMR- enables wide variation of solution conditions; direct characterization of motions and of weakly interacting systems • Computation- fundamental understanding of structure, dynamics and interactions; models without experiment; fast

  11. Challenges For Understanding The Meaning of Structure • Structures determined by NMR, computation, and X-ray crystallography are static snapshots of highly dynamic molecular systems • Biological process (recognition, interaction, chemistry) require molecular motions (from femto-seconds to minutes) • New methods are needed to comprehend and facilitate thinking about the dynamic structure of molecules: visualization

  12. Visualization of Structures Intestinal Ca2+-binding protein! • Need to incorporate 3D and motion

  13. Calcium-Dependent Protein KinaseA Target for Anti-Malarial Drug Design

  14. Calcium Signal Transduction EF-Hand Ca2+ Sensors Ca2+ Target (kinase)

  15. Regulation of Protein Kinase Activity by Ca2+-Calmodulin Ca2+ signal Kinase Activation

  16. Kinase Protozoa Have A Unique Kinase The Ca2+-Dependent Protein Kinase (CDPK) Standard auto- inhibitory segment Calmodulin-like domain (CaM-LD) • CDPK has its own regulatory apparatus!! • How does it work?

  17. Structure of CDPK RevealsIntra-molecular Kinase Activation

  18. CaM-LD Calmodulin Anti-Malarial Drug DesignMust Inhibit CaM-LD But Not Calmodulin

  19. Center for Structural BiologyA Trans-Institutional Initiative • Increase molecular/physical thinking in medical and biological research • Foster multi-disciplinary approaches • Focal point bridging medicine and biology to physics and chemistry

  20. Structural Biology ResourceBut Not A Core!! • Education/project origination • Enabling expertise: 3 Ph.D. Staff Scientists • Enabling hardware: technologies to visualize and determine structures • Open-access focal point in BIOSCI/MRBIII

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