An introduction to molecular biology . . . Bi 150 Lecture 0 October 4, 2012 An introduction to molecular biology . . . but you will learn the cell biology in this course

3 x 109 base pairs Lander et al

Males are XY; females are XX. Humans have 22 pairs of chromosomes, plus the X and Y. Males are XY; females are XX. A. Each chromosome is “painted” with a unique combination of fluorescent dyes B. We have arranged the chromosomes to form pairs. © Garland; Little Alberts Fig 5-12

Genes can be localized crudely by hybridizing a fluorescent nucleotide probe to chromosomes 2 mm 6 distinct genes are probed in this image Little Alberts Fig 10-16 Seuss 1959

Complete DNA sequence as scripture (surf NCBI) orthologs in other species single-nucleotide polymorphisms (SNPs) mutations that cause disease chromosomal location basic sequence proteins that bind to the sequence and regulate expression RNA splicing RNA sequence RNA abundance protein sequence protein function protein structure

How much coding sequence is in the genome? 22,000 genes x 400 codons/protein x 3 bases/codon = 26.4 million base pairs, or < 1% of the genome! The remainder . . . 1. Repetitive elements (junk? selfish DNA?) 2. Regulatory regions 3. Introns

Gene activation involves regulatory regions Little Alberts Fig. 8-15 © Garland publishing

untranslated sequences Components of Expression coding sequences noncoding sequences Gene (DNA) exon intron transcription (mRNA synthesis) splicing (introns removed) messenger RNA (mRNA) translated sequences untranslated sequences translation protein

Protein synthesis and degradation A. synthesis B. degradation “proteolysis” protein + Greek, breakdown Modified from Little Alberts Panel 2-5

the tRNA synthetase translates the genetic code, because it contacts (a) the amino acid (c) in some cases, other parts of the tRNA (b) the anticodon loop

Most drug receptors are proteins. a molecule on the cell surface or in the cell interior that has an affinity for a specific molecule (the ligand). Latin, “to tie” Most drug receptors are proteins. Greek, “first”

shortest: 9 longest: 5500 “peptide” or amide bonds 20 types link the “backbone” “main chain” “a-carbons” side chains 20 types Little Alberts Figure 2-22 © Garland publishing

Proteins contain a few structural motifs: a helices b sheets (A protein viewer must be installed on your computer) http://www.its.caltech.edu/~lester/Bi-1/alpha-helix-alphabetical.pdb http://www.its.caltech.edu/~lester/Bi-1/beta-sheet-antiparallel.pdb Hide side chains Show H-bonds and distances Show ribbons & arrows Show side chains Show Van der Waals radii

Most drug receptors are membrane proteins nicotine, another agonist nicotinic acetylcholine receptor Outside the cell natural ligand (agonist) ~ 100 Å = 10 nm Membrane = lipid bilayer Inside the cell = cytosol (view in ~1995)

Several ways to make an arch Protein Folding vs. “Inverse Folding” = Computational Protein Design Protein Folding (no degeneracy) Inverse Folding (large degeneracy) Set of All Structures Set of All Sequences Individual amino acids Several ways to make an arch

G protein-coupled receptor membrane A future Lecture receptor t s q i G protein enzyme channel effector kinase phosphorylated protein cAMP Ca2+ intracellular messenger cytosol The pathway from a G protein-coupled receptor (GPCR) to gene activation nucleus How fast? 10 s to days How far? Up to 1 m

Protein degradation is accomplished primarily by proteolytic enzymes The genome encodes hundreds of proteolytic enzymes. They vary in -- sequence specificity for the “cut” -- cellular expression -- organelle of expression

Cells often mark proteins for proteolysis by attaching strings of the protein, ubiquitin. strings of ubiquitiin to be proteolyzed other protein modified from Little Alberts Fig 18-7

Controlled proteolysis takes place in the proteasome shorter modified from Little Alberts 1st edition Fig 7-32

Atomic-scale Structures procaine morphine botulinum toxin nicotine (Download to your computer; Then open with Swiss-prot pdb viewer) http://www.its.caltech.edu/~lester/Bi-1/morphine.pdb http://www.its.caltech.edu/~lester/Bi-1/procaine.pdb http://www.its.caltech.edu/~lester/Bi-1/nicotine.pdb