Chapter 02

Genomics and Proteomics

Fig 2-4: Superposition of structures of histidine-containing phosphocarrier proteins from Escherichia coli [1poh] (black) and Streptococcus faecalis [1ptf] (red). Although over 60% of the residues have mutated, the folding pattern is completely intact.

Fig 2-5: Model of the FtsZ protofilament, based on the crystal structure of the Methanococcus jannaschii monomer [1fsz], four subunits assembled by homology with tubulin. I thank J. Löwe and L. Amos for the coordinates.

Fig 2-6a: The coiled-coil structure of &alpha-keratin also appears in the eukaryotic transcriptional activator GCN4 [2zta]. This structure contains two helices coiled around each other. It is known as the 'leucine zipper' because of the leucine repeats every 7 residues (shown in ball-and-stick representation). The pitch is 14.7 nm.

Fig 2-7: The structure of collagen, a three-stranded supercoil formed by braiding together three polypeptide chains. In each strand, the rise per residue is approximately 0.3 nm. Each polypeptide chain itself forms a helix, with approximately 3.3 residues per turn. The repeat distance of the supercoil is approximately 1 nm [1bkv].

Fig 2-8: An enzyme-substrate complex: E. coli N-acetyl-L-glutamate kinase binding the substrate N-acetylglutamate and the inhibitory cofactor analogue AMPPNP (instead of the natural cofactor ATP) [1gs5]. The substrate and inhibitor nestle snugly into the enzyme, which holds them in proper proximity for phosphate transfer. (a) The substrate and cofactor analogue occupy a crevice in the molecule. (b) The mainchain and sidechains that surround the ligands.

Fig 2-10: Thrombin, a key player in the control of blood coagulation, is a member of the chymotrypsin family of serine proteinases. The active site lies in a cleft between two domains. The two domains are homologues, that arose by gene duplication and divergence. Human thrombin binds the synthetic inhibitor hirulog-3, a 20-residue peptide related to the natural inhibitor hirudin from the leech [1abi]. Hirulog interacts with both the catalytic site and an anion-binding exosite specific to thrombin.

Fig 2-11: HIV-1 proteinase binds a stable macrocyclic inhibitor that mimics a tripeptide moiety of the natural substrate [1d4k].

Fig 2-12: Retinol-binding protein [1rbp]. is an example of a &beta-barrel, in which the strands of a &beta-sheet are wrapped around into a cylinder, with continuous lateral hydrogen bonding around the circumference of the barrel. By forming barrels of different sizes, from different numbers of strands, proteins can create interior cavities of different sizes to bind different ligands.

Fig 2-14: The structure of bacteriorhodopsin from Halobacterium salinarum [2brd], illustrating the common theme of a 7-transmembrane helix structure. Bacteriorhodopsin is a light-driven pump, converting light energy absorbed by the chromophore, retinal, to a proton gradient across the membrane.

Fig 2-15: The structure of E. coli outer membrane protein A (ompa) [1qjp], a &beta-barrel protein traversing the cell membrane. Ompa appears in gram negative bacteria as a structural membrane protein interacting with lipoproteins, and also serves as a docking site for the bacteriocidal protein colicin, and some phages, and is also involved in conjugation.

Fig 2-17: Human growth hormone (blue) in complex with two molecules illustrating the dimerized exterior domain of its receptor [3hhr].

Fig 2-18: p21 Ras binding GTP. Although an active GTPase the system was stabilized for crystal-structure analysis by cooling to 100 K [1qra].

Fig 2-19: The conformational change in p21 Ras from the inactive GDP-binding conformation to the active GTP-binding conformation primarily involves two regions (shown here in red), that form a patch on the molecular surface [1qra] and [1q21].

Fig 2-20: Comparison of the folding patterns of two small proteins. (a) Cow acylphosphatase [2acy]. (b) Viral toxin from corn smut fungus (Ustilago maydis) [1kpt]. Although there are many superficial similarities between the folding patterns of these two proteins, they have different topologies (unlike the two related proteins in Figure 2-4).

Fig 2-21: All-atom representation of corn smut fungal toxin [1kpt]. In contrast to the representation of this protein in the previous figure, this picture shows the compactness of the packing of the structure, and the topography of the surface; but it would be difficult to trace the chain in this picture. Can you see an &alpha-helix? (Not easy, but it's there.)

Comparison of the folding patterns of acylphosphatase and the fungal toxin. Acylphosphatase [2acy]. Corn smut fungal toxin [1kpt].

Fig 2-22: Proteins from the globin family assemble different combinations of oligomers. (a) monomer: Sperm whale myoglobin [1mbo]. (b) dimer of two identical subunits: Ark clam globin [4sdh] (c) mixed tetramer: Human haemoglobin [1hho] containing two &alpha chains and two &beta chains.

Fig 2-23: Antibody molecule, illustrating both the concatenation of domains within each of the four chains, and the formation of a dimer [1igt]. Like haemoglobin, this molecule is a dimer of dimers, containing two identical light chains and two identical heavy chains. The antigen-binding sites are at the 'wingtips'.

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Chapter 02