Fundamentals of Fundamentals of Protein StructureProtein Structure

August, 2006

Tokyo University of Science Tadashi Ando

Our life is maintained by Our life is maintained by molecular network systemsmolecular network systems

Molecular network system in a cell

(From ExPASy Biochemical Pathways; http://www.expasy.org/cgi-bin/show_thumbnails.pl?2)

Proteins play key roles in a Proteins play key roles in a living systemliving system

Three examples of protein functions

Catalysis:Almost all chemical reactions in a living cell are catalyzed by protein enzymes.

Transport:Some proteins transports various substances, such as oxygen, ions, and so on.

Information transfer:For example, hormones.

Alcohol dehydrogenase oxidizes alcohols to aldehydes or ketones

Haemoglobin carries oxygen

Insulin controls the amount of sugar in the blood

Amino acid: Basic unit of Amino acid: Basic unit of proteinprotein

COO-NH3+ C

R

HAn amino

acid

Different side chains, R, determin the properties of 20 amino acids.

Amino group Carboxylic acid group

20 20 Amino acidsAmino acidsGlycine

(G)

Glutamic acid (E)Asparatic acid (D)

Methionine (M)

Threonine (T)

Serine (S)

Glutamine (Q)

Asparagine (N)

Tryptophan (W)Phenylalanine (F)

Cysteine (C)

Proline (P)

Leucine (L)Isoleucine (I)Valine (V)

Alanine (A)

Histidine (H)Lysine (K)

Tyrosine (Y)

Arginine (R)

White: Hydrophobic, Green: Hydrophilic, Red: Acidic, Blue: Basic

Proteins are linear polymers Proteins are linear polymers of amino acidsof amino acids

R1

NH3＋

C CO

H

R2

NH C CO

H

R3

NH C CO

H

R2

NH3＋

C COOー

H＋

R1

NH3＋

C COOー

H＋

H2OH2O

Peptide bond

Peptide bond

The amino acid sequence is called

as primary structure A AF

NGG

S TS

DK

A carboxylic acid condenses with an amino group with the release of a water

Amino acid sequence is Amino acid sequence is encoded by DNA base encoded by DNA base sequence in a genesequence in a gene

・CGCGAATTCGCG・

・GCGCTTAAGCGC・

DNA molecule

＝

DNA base sequence

Amino acid sequence is Amino acid sequence is encoded by DNA base encoded by DNA base sequence in a genesequence in a gene

Second letterT C A G

Firs

t lette

r

T

TTTPhe

TCT

Ser

TATTyr

TGTCys

T

Th

ird le

tter

TTC TCC TAC TGC CTTA

LeuTCA TAA

StopTGA Stop A

TTG TCG TAG TGG Trp G

C

CTT

Leu

CCT

Pro

CATHis

CGT

Arg

TCTC CCC CAC CGC CCTA CCA CAA

GlnCGA A

CTG CCG CAG CGG G

A

ATTIle

ACT

Thr

AATAsn

AGTSer

TATC ACC AAC AGC CATA ACA AAA

LysAGA

ArgA

ATG Met ACG AAG AGG G

G

GTT

Val

GCT

Ala

GATAsp

GGT

Gly

TGTC GCC GAC GGC CGTA GCA GAA

GluGGA A

GTG GCG GAG GGG G

Gene is protein’s Gene is protein’s blueprint, genome is life’s blueprint, genome is life’s

blueprint blueprint

Gene

GenomeDNA

Protein

Gene GeneGene

Gene

GeneGeneGeneGene

GeneGeneGeneGene

GeneGene

Protein Protein

ProteinProtein

Protein

ProteinProtein

Protein

Protein

Protein

Protein

ProteinProtein

Protein

Gene is protein’s Gene is protein’s blueprint, genome is life’s blueprint, genome is life’s

blueprint blueprint Genome

Gene GeneGene

Gene

GeneGeneGeneGene

GeneGeneGeneGene

GeneGene

Protein Protein

ProteinProtein

Protein

ProteinProtein

Protein

Protein

Protein

Protein

ProteinProtein

Protein

Glycolysis network

3 billion base pair => 6 G letters &

1 letter => 1 byte

The whole genome can be recorded in just 10 CD-ROMs!

In 2003, Human genome In 2003, Human genome sequence was sequence was deciphered!deciphered!

Genome is the complete set of genes of a living thing.In 2003, the human genome sequencing was completed.The human genome contains about 3 billion base pairs.The number of genes is estimated to be between 20,000 to 25,000.The difference between the genome of human and that of chimpanzee is only 1.23%!

Each Protein has a unique Each Protein has a unique structurestructure

Amino acid sequence

NLKTEWPELVGKSVEEAKKVILQDKPEAQIIVLPVGTIVTMEYRIDRVRLFVDKLDNIAE

VPRVGFolding!

Basic structural units of Basic structural units of proteins: Secondary structureproteins: Secondary structure

α-helix β-sheet

Secondary structures, α-helix and β-sheet, have regular hydrogen-bonding patterns.

Three-dimensional Three-dimensional structure of proteinsstructure of proteins

Tertiary structure

Quaternary structure

Hierarchical nature of Hierarchical nature of protein structureprotein structure

Primary structure (Amino acid sequence)↓

Secondary structure （ α-helix, β-sheet ）↓

Tertiary structure （ Three-dimensional structure formed by assembly of secondary

structures ）↓

Quaternary structure （ Structure formed by more than one polypeptide chains ）

Close relationship between Close relationship between protein structure and its protein structure and its

functionfunction

enzyme

A

B

A

Binding to A

Digestion of A!

enzyme

Matching the shape to A

Hormone receptor AntibodyExample of enzyme reaction

enzyme

substrates

Protein structure prediction has Protein structure prediction has remained elusive over half a remained elusive over half a

centurycentury

“Can we predict a protein structure from its amino acid sequence?”

Now, impossible!

SummarySummaryProteins are key players in our living systems.Proteins are polymers consisting of 20 kinds of amino acids.Each protein folds into a unique three-dimensional structure defined by its amino acid sequence.Protein structure has a hierarchical nature.Protein structure is closely related to its function.Protein structure prediction is a grand challenge of computational biology.