BioinformaticsCh1. Introduction (continue-2)

阮雪芬Nov7, 2002NTUST

www.ntut.edu.tw/~yukijuan/lectures/bioinfo/Nov7.ppt

Searching for Similar Sequences in Databases: PSI-BLAST

Determine the sequence of a new gene Identify within the human genome a gene responsible for some disease

To determine whether related genes appear in other species

The ideal method is1. Sensitive2. Selective

Searching for Similar Sequences in Databases: PSI-BLAST A powerful tool for searching sequence

databases with a probe sequence is PSI-BLAST

BLAST: An earlier program worked by identifying local regions of similarity without gaps and then piecing them together.

PSI-BLAST: refer to enhancements that identify patterns within the sequences at preliminary stages of the database search, and then progressively refine them.

Ex. 1.4

P26367

Ex. 1.4

PAX-6

Ex. 1.4

Sequence

PSI- and PHI-BLAST

http://www.ncbi.nlm.nih.gov/blast/index.html

Ex. 1.4

gi|1352719|sp|P47237|PAX6_CHICK Paired box protein Pax-6 379 e-105

Ex. 1.4

EX.1.5

What species contain homologues of human PAX-6 detectable by PSI-BLAST?

EX.1.5

EX.1.5

EX.1.5

Introduction to Protein Structure Protein Function:

Structural proteins Catalyse chemical reactions Transport and storage proteins Regulatory proteins

Hormones Receptor/signal transduction proteins

Control genetic transcription Protein involved in recognition

cell adhesion molecules Antibodies and other proteins of the immune

system

Primary Structure

Peptide-bond Formation

Amino Acid Sequences Have Direction

Components of a Polypeptide Chain

•Backbone: constant•Side chains: variable

Introduction to Protein Structure

Proteins are large molecules

(backbone)

Secondary Structure

-helix -sheet

Supersecondary structure

-helix hairpin -helix hairpin unit

Domains Many proteins

contain compact units within the folding pattern of a single chain, that look as if they should have independent stability.

The cell-surface protein CD4 consists of four similar domains

Modular proteins

Modular proteins are multidomain proteins which often contain many copies of closely related domain.

Fibronectin: a large extracellular protein involved in

cell adhesion and migration contains 29 domains including multiple

tandem repeats of three typesof domains called F1, F2 and F3

http://www.bork.embl-heidelberg.de/Modules/07-matrix.gif

Classification of Protein Structure

Occupies a key position in bioinformatics, not least as a bridge between sequence and function

Divide the Proteins into Domains

Protein Structure Prediction and Engineering

Secondary structure prediction

Fold recognition Homology

modelling

Protein Structure Prediction and Engineering

Critical Assessment of Structure Prediction (CASP)

Protein engineering

Clinical Implications

Categories of applications Diagnosis of disease and disease risks Genetics of responses to therapy Identification of drug targets Gene therapy

Diagnosis of Disease and Disease Risks

DNA sequencing can detect the absence of a particular gene, or a mutation

Identification of specific gene sequences associated with disease

In many cases our genes do not irrevocably condemn us to contract a disease, but raise the probability that we will. 1-antitrypsin: inhibit elastase in the alveoli of

the lung

A combination of genetic and environmental factors

Genetics of Responses to Therapy

Customized treatment Sequence analysis permits selecting

drugs and dosages optimal for individual patients---pharmacogenomics

The very toxic drug 6-mercaptopurine is used in the treatment of childhood leukaemia

Lack Thiopurine methyltransferase

Die

Identification of Drug Targets

A target is a protein the function of which can be selectively modified by interaction by a drug, to affect the symptoms or underlying causes of a diease.

Gene Therapy

A gene is missing or defective replace it

A gene is overactive turn it off