1. Structural Biomedicine
Protein-based
Structural Biomedicine
Lucy Malinina
Structural Biology UNIT
CIC bioGUNE
Bilbao, Spain

2. Structural Biomedicine
Protein-based
Structural Biomedicine
is a part of STRUCTURAL BIOLOGY aimed at using structural knowledge to control and pharmacologically modulate protein properties

3. Manipulating Protein Specificity
||||||||| Protein-Lipid Selectivity |||||||||||||||
|||||||||| Protein-RNA specificity ||||||||||||||||

4. PART I. Introduction to STRUCTURAL BIOLOGY
PART II. GLTP, GlycoLipid Transfer Protein
PART III. P19, suppressor of RNAi

5. makes known the structure of biomolecules
STRUCTURAL BIOLOGY
makes known the structure of biomolecules
structure determination
structure analysis:
i) description
ii) relationship to function
iii) generalizations

6. Basic techniques of STRUCTURAL BIOLOGY
Molecules, complexes, assemblies - as single crystals
Macromolecular X-ray Crystallography
Electron Microscopy - EM
Nuclear Magnetic Resonance - NMR
Useful for very large assemblies, where X-ray crystallography becomes very difficult
Molecules in solution; useful to study flexible parts, invisible for X-ray crystallography

7. CRYSTALIZATION
X-RAY DATA COLLECTION
“SOLVING” THE STRUCTURE
With X-rays, we can detect diffraction from molecules, but we then have to apply some experimental tricks to solve a phase problem and use a computer to reassemble the image. This is the essence of the X-ray macromolecular crystallography

8. DNA double helix: A, B, Z

9. Stem-loop RNA structure, hairpin

10. RNA molecules are not double helices, neighter single strands
RNA molecules are not double helices, neighter single strands. RNAs are “highly structured”.
Ribozyme

11. PROTEINS

12. -Helix

13. -Structure

14. Turns

15. Loops
are often flexible
and therefore disordered in crystals

16. Viral suppressor of RNAi p19

17. FOLDS
DOMAINS
MOTIVES

18. OB-fold N C β1 β2 β3 β4 β5
α34
L12
L45

19. Structural conservation between
RPA70
OB-B / ssDNA
RPA32 core
(OB-D)
RPA14
L45 5’
W361 3’
F386
300
420