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    Medicine and Biology at The Atomic Scale

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    raminehal
    This document discusses how structural biology uses atomic structures to understand how biomolecules communicate. It examines how x-ray crystallography, NMR spectroscopy, and computation are used to determine 3D structures of biomolecules. Understanding molecular structures provides insight into biological processes and pathways. The calcium-dependent protein kinase is discussed as a target for anti-malarial drug design since its structure reveals how it is activated without calcium/calmodulin. The Center for Structural Biology aims to increase molecular thinking in medicine and biology through multi-disciplinary collaboration.

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    Medicine and Biology at The Atomic Scale

    Uploaded by

    raminehal
    27 views20 pages
    This document discusses how structural biology uses atomic structures to understand how biomolecules communicate. It examines how x-ray crystallography, NMR spectroscopy, and computation are used to determine 3D structures of biomolecules. Understanding molecular structures provides insight into biological processes and pathways. The calcium-dependent protein kinase is discussed as a target for anti-malarial drug design since its structure reveals how it is activated without calcium/calmodulin. The Center for Structural Biology aims to increase molecular thinking in medicine and biology through multi-disciplinary collaboration.

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    Biomed.Informatics

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    This document discusses how structural biology uses atomic structures to understand how biomolecules communicate. It examines how x-ray crystallography, NMR spectroscopy, and computation are used to determine 3D structures of biomolecules. Understanding molecular structures provides insight into biological processes and pathways. The calcium-dependent protein kinase is discussed as a target for anti-malarial drug design since its structure reveals how it is activated without calcium/calmodulin. The Center for Structural Biology aims to increase molecular thinking in medicine and biology through multi-disciplinary collaboration.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    27 views20 pages

    Medicine and Biology at The Atomic Scale

    Uploaded by

    raminehal
    This document discusses how structural biology uses atomic structures to understand how biomolecules communicate. It examines how x-ray crystallography, NMR spectroscopy, and computation are used to determine 3D structures of biomolecules. Understanding molecular structures provides insight into biological processes and pathways. The calcium-dependent protein kinase is discussed as a target for anti-malarial drug design since its structure reveals how it is activated without calcium/calmodulin. The Center for Structural Biology aims to increase molecular thinking in medicine and biology through multi-disciplinary collaboration.

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    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*
    High Resolution Structural Biology
    Using atomic structure to understand how
    biomolecules communicate
    The Reward: Understanding→Control
    Anti-tumor Activity
    Duocarmycin SA

    Atomic interactions

    Shape
    Hierarchy of Structural Biology

    NER
    RPA
    BER
    RR

    Molecule Pathway Activity


    Structural Genomics Structural Proteomics Systems Biology
    High Resolution Structural Biology
    Three Complementary Techniques

    NMR Spectroscopy X-ray Crystallography

    Computation

    Determine experimentally or model


    3D structures of biomolecules
    What Tools Do We Use?
    Expression/Mutations Biophysical Analysis Crystallography

    Fluorescence Intensity
    RPA-A

    RPA-B

    RPA-AB

    Ratio of T-ag/RPA

    NMR Computation
    Experimental Determination
    of 3D Structures
    X-ray NMR

    RF
    Diffraction
    X-rays RF Signals
    Pattern

    H0

    Direct detection of Indirect detection of


    atom positions H-H distances
    Crystals In solution
    Representations of Structure
    Conformational Ensemble

    Neither crystal nor


    solution structures
    are properly
    represented by a
    single conformation
     Intrinsic motions
     Imperfect data

    PRECISION
    RMSD of the ensemble
    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
    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
    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
    Visualization of Structures

    Intestinal Ca2+ -binding protein!

     Need to incorporate 3D and motion


    Calcium-Dependent Protein Kinase
    A Target for Anti-Malarial Drug Design
    Calcium Signal Transduction
    EF-Hand Ca2+ Sensors

    Ca2+

    Target
    (kinase)
    Regulation of Protein Kinase
    Activity by Ca -Calmodulin
    2+

    Ca2+ signal

    Kinase Activation
    Protozoa Have A Unique Kinase
    The Ca2+ -Dependent Protein Kinase (CDPK)
    Standard auto-
    inhibitory segment
    Calmodulin-like
    domain (CaM-LD)

    Kinase

     CDPK has its own regulatory apparatus!!


    How does it work?
    Structure of CDPK Reveals
    Intra-molecular Kinase Activation
    Anti-Malarial Drug Design
    Must Inhibit CaM-LD But Not Calmodulin

    Calmodulin CaM-LD
    Center for Structural Biology
    A 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
    Structural Biology Resource
    But 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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