Levels of protein structure by Pradeepan Ramasamy

1. LEVELS OF PROTEIN
STRUCTURE
PRESENTED BY
PRADEEPAN R
M.PHARM 2ND SEMESTER
DEPARTMENT OF PHARMACOLOGY
COP SRIPMS
1

2. CONTENTS
INTRODUCTION
STRUCTURE OF PROTEIN
LEVELS OF PROTEIN STRUCTURE
ROLE OF PROTEIN STRUCTURE IN DRUG DESIGN
CONCLUSION
BIBLIOGRAPHY
2

3.  Major structural and functional aspects of the body
 Our 3/4th dry body weight are made of proteins
 Major components - Carbon, Hydrogen, Oxygen and Nitrogen
 All proteins are polymers of amino acids.
“proteios” - primary or first
3
INTRODUCTION

4. AMINO ACID
Amino acids are building blocks of protein
4

5. PEPTIDE BOND FORMATION
Amino acids are joined together to form a polypeptide chain by peptide bond.
5

6. 6
CHAIN FORMATION

7. POLYPEPTIDES
Polypeptide chains - Chains having less than 40-50 amino acids.
Larger than this size, they are called proteins.
Proteins - long polypeptide chains.
The structure, function and general properties of a protein are all
determined by the sequence of amino acids.
7

8. LEVELS OF PROTEIN STRUCTURE
8

9. PRIMARY STRUCTURE
 Sequence of amino acids
Example: Gly - Ala - Val (1)
Gly - Val - Ala (2)
 Largely responsible for protein function
 Change in protein sequence –Affects
protein’s overall structure &function.
Example – Sickle cell anaemia
9

10. A chain - 21 amino acids
B chain - 30 amino acids
Interchain disulfide bonds – 7Cys A & 7Cys B, 20Cys A & 19Cys B
BRANCHED PROTEINS – HUMAN INSULIN
7
7
20
6 11
19
21 amino acids
30 amino acids
10
Ile
Thr

11. CIRCULAR PROTEINS - PROINSULIN
Proinsulin is a single polypeptide chain with 86 amino acids
Removal of C peptide
11

12. Even a single amino acid change (mutation) in the linear sequence
may have profound biological effects
Example: Sickle cell anaemia (change in 2 amino acids out of 600).
12
ROLE OF PRIMARY STRUCTURE IN BIOLOGICALACTIVITY

13. SECONDARY STRUCTURE
Primary sequence or main chain of the protein must
organize itself to form a compact structure
Polypeptide chain by twisting or folding is referred to as
secondary structure.
Two types of secondary structure
α - Helix β – Pleated
sheets
13

14. Spiral structure of protein
Tightly packed coiled structure
Stabilized by extensive hydrogen bonding
Each turn of α -helix contains 3.6 amino acids
The spacing of each amino acid is 0.15 nm
The right handed α-helix is more stable than left handed helix
Proline – Helix breaker (not compatible with helix)
α - HELIX
14

15.  Two or more segments of fully extended peptide chains
 Sheet-like structure held together by hydrogen bonds
 The distance between adjacent amino acids is 3.5Å
 Two types-
β – PLEATED SHEETS
• Parallel sheets
• Anti parallel sheets
15

16. PARALLEL & ANTI PARALLEL BETA SHEETS
16
OTHER ELEMENTS
β – Turns

17. Flavodoxin
Collagen
Examples of Secondary structure
17

18. TERTIARY STRUCUTURE
Three-dimensional arrangement of protein structure
Secondary structure elements come together to form the tertiary structure
Stability of structure
• Hydrogen bonds
• Ionic bonds
• Dipole-dipole interactions
• Hydrophobic interactions
• Disulfide bonds (safety pins)
18

19. MYOGLOBIN
 It has 154 amino acids residues
 Myoglobin contains a heme (prosthetic) group
 Oxygen bound myoglobin is called oxymyoglobin
19

20. • Pairs of cysteines can form disulfide bonds
between different parts of the main chain
• This adds stability and is common in
extracellular proteins
DISULFIDE BONDS
20

21. HYDROGEN BONDING
Hydrogen bonding is a special
type of dipole-dipole
attraction between molecules,
not a covalent bond to a
hydrogen atom.
Ionic bonding is the
complete transfer of
valence electron(s) between
atoms
IONIC BONDING
21

22. Not attractive interactions, but results
from inability of water to form
hydrogen bonds with side chains.
Intermolecular forces that occurs
between atoms and non polar molecules
as a result of motion of electrons.
HYDROPHOBIC INTERACTIONS VAN DER WAALS INTERACTIONS
22

23. QUATERNARY STRUCTURE
Polypeptides aggregates together to form one functional protein
Each polypeptide chain is called as subunit or monomers
Structure may be monomer, dimer, trimer, tetramer and so on
 Hydrogen bonds
 Electrostatic bonds
 Hydrophobic bonds
 Van der waals forces
SOURCES STABILIZING STRUCUTRE
23

24.  Two identical α and β chains
 Subunit is linked covalently to molecule of heme
 Held together by
Hydrophobic interactions
Hydrogen bonding
Salt bridges
HAEMOGLOBIN
α chain - 141 amino acids
β chain - 146 amino acids
24

25. OTHER EXAMPLES
Creatine kinase Lactate dehydrogenase
Immunoglobulin G
25

26. ROLE OF PROTEIN STRUCTURE IN DRUG DESIGN
Structure based drug design:
Ligand based drug design
Receptor based drug design
Computer aided drug design:
Docking
Denovo Drug design
26
Protein structure – Core of drug design

27. STRUCTURE BASED DRUG DESIGN
 Knowledge of 3D structure of biological target
 Obtained by protein prediction
Ligand based design Receptor based design
• Finding ligand for receptor
• Large number of potential Ligand
screening
• Building ligands according to receptor
• Ligands are built by small pieces in a
stepwise manner
• This pieces may be Individual Atoms
or Molecular fragments
27

28. Pharmacophore
identification
Pharmacophore
modification
Fit for the
receptor
Potential Drug
Active site
identification
Ligand fragments
Building
Fit for the
receptor
Change fragment
Potential Drug
No
Yes
Yes
No
Flow chart of two strategies of Structure based drug design
28

29. COMPUTER AIDED DRUG DESIGN
Docking
Ability to position a ligand in a active site or
a designated site of protein
Calculating the specific binding affinities
29
Denovo Drug design
Iterative process using 3D structure of
target to find new medications

30. CONCLUSION
Protein structure plays a key role in biochemistry studies
It plays a key role in drug design
Without protein structure drug design cannot be done
The primary use of protein structure for the development of drug
compounds is to determine the structure of a protein in complex with
a tool compound
30

31. BIBLIOGRAPHY
Andreeva A. Lessons from making the Structural Classification of Proteins (SCOP)
and their implications for protein structure modelling: Biochem Soc Trans.
2016: 15(43): 937-45.
Chothia C. Hubard T. Brenner S. Barns. Murzin A. Protein Folds in the α and β
classes: Annu. Rev. Biophys. Biomol. Struct. 1997: 26; 597-627.
Satyanarayana U. Chakrapani U. Biochemistry. Proteins and amino acids: 4th ed. New
Delhi; Reed Elsevier India private Limited; 2013.
Staker BL. Buchko GW. Myler PJ. Recent contributions of Structure-Based Drug
Design to the development of antibacterial compounds: Curr Opin Microbiol.
2015: 27; 133-8.
Vasudevan DM. Sreekumari S. Vaidyanathan K. Textbook of biochemistry for medical
students: Proteins: Structure and Function. 8thed. New Delhi; Jaypee brothers
publications (P) Ltd.; 2017.
31