Structural Biology UNITCIC bioGUNEBilbao, Spain

Lucy Malinina

lucy@cicbiogune.es

Protein-based Structural Biomedicine

is a part of STRUCTURAL BIOLOGY

aimed at using structural knowledge to

control and pharmacologically modulate

protein properties

is a part of STRUCTURAL BIOLOGY

aimed at using structural knowledge to

control and pharmacologically modulate

protein properties

Manipulating Protein SpecificityManipulating Protein Specificity

|||||||||| Protein-RNA specificity |||||||||||||||||||||||||| Protein-RNA specificity ||||||||||||||||

||||||||| Protein-Lipid Selectivity |||||||||||||||||||||||| Protein-Lipid Selectivity |||||||||||||||

PART I. Introduction to STRUCTURAL BIOLOGY

PART II. GLTP, GlycoLipid Transfer Protein

PART III. P19, suppressor of RNAi

PART I. Introduction to STRUCTURAL BIOLOGY

PART II. GLTP, GlycoLipid Transfer Protein

PART III. P19, suppressor of RNAi

STRUCTURAL BIOLOGY

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

• structure determination• structure analysis:

i) description ii) relationship to

function iii) generalizations

Basic techniques of STRUCTURAL BIOLOGY

•Macromolecular X-ray Crystallography

•Electron Microscopy - EM

•Nuclear Magnetic Resonance - NMR

Useful for very large assemblies, where X-ray crystallography becomes very difficult

Molecules, complexes, assemblies - as single crystals

Molecules in solution; useful to study flexible parts, invisible for X-ray crystallography

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

CRYSTALIZATION

X-RAY DATA COLLECTION

“SOLVING” THE STRUCTURE

DNA double helix: A, B, Z

Stem-loop RNA structure, hairpin

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

PROTEINS

-Helix

-Structure

Turns

Loops

are often flexible

and therefore disordered in crystals

Viral suppressor of RNAi p19

FOLDS

DOMAINS

MOTIVES

OB-fold

N

C

β1

β2

β3

β4

β5

α34 L12

L45

RPA32 core(OB-D)

RPA14

Structural conservation between

RPA70OB-B / ssDNA

W361

F386

5’

3’

300

420

L45