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Using Structure to Elucidate Function/Mechanism

Using Structure to Elucidate Function/Mechanism. An experimental strategy for. determining the arrangement of atoms/molecules in space to obtain structural information. Some situations in which this strategy might be applied. understand a mechanism in detail

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Using Structure to Elucidate Function/Mechanism

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  1. Using Structure to Elucidate Function/Mechanism

  2. An experimental strategy for • determining the arrangement of atoms/molecules in space to obtain structural information

  3. Some situations in which this strategy might be applied • understand a mechanism in detail • structure-based (rational) drug design • elucidate a novel structure • understand a conformational switch (e.g. prions)

  4. Some methods that provide structural information: • X ray bombardment of crystals • circular dichroism (CD) • nuclear magnetic resonance (NMR)- size < 25 kD • sequence comparison/analysis (e.g. COILS or threading)- surface residues are most conserved • electron microscopy (EM) • atomic force microscopy • photo/chemical cross-linking • protease digestion • calorimetry • sedimentation

  5. Circular Dichroism The differential absorption of radiation polarized in two directions as a function of frequency is called dichroism.Circular dichroism (CD) spectroscopy is a form of light absorption spectroscopy that measures the difference in absorbance of right- and left-circularly polarized light (rather than the commonly used absorbance of isotropic light) by a substance. http://broccoli.mfn.ki.se/pps_course_96/ss_960723_21.html Kurt D. Berndt

  6. Circular Dichroism Circular dichroism is very sensitive to the secondary structure of polypeptides and proteins. http://broccoli.mfn.ki.se/pps_course_96/ss_960723_21.html Kurt D. Berndt

  7. What are the experimental prerequisites for structural studies? • material for study should be of homogeneous composition. How? • often useful to reduce the complexity of the problem by focusing on a subregion of a larger molecule. How? • minimize flexibility of the molecule in solution so that only a small number of conformations are possible. How?

  8. What are possible pitfalls of crystallographic studies? • biologically irrelevant structure? Less common than you might think. • faulty interpretation. Interfaces that form during packing of molecules into a crystal may not be biologically relevant. Solution?

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