Prehistory

• Ph.D. with Peter Pauling, at University College London. ‘The crystal structures of some molecules active at cholinergic nerve receptors’, 1973

• Post-doc at LMB with David Blow• Collaborations with Fred Richards

(Yale), Michael Levitt (Weizmann Institute of Science), Joël Janin (Institut Pasteur, Paris)

• Return to England in 1976 …

220 – 175 + 1 = 46

270 – 225 + 1 = 46

46 + 46 = 92

Sperm whale myoglobin (yellow)

Lupin leghaemoglobin (red)

Importance of helix-helix contacts as determinants of structure

· Residue packing at helix interfaces produces discrete geometries of interhelical angles

Poplar leaf plastocyanin Alcaligenes denitrificans azurin

Insulin4-Zn form

Courtesy Nature Publishing Group

Insulin4-Zn form

Complete IgG [1IGT]

Six antigen-binding loops, or complementarity-determining regions (CDRs)

The canonical-structure model

· Five of the six antigen-binding loops – L1, L2, L3, H1 and H2, but NOT H3 – have individual discrete, small conformational repertoires, a set of canonical structures.

· The conformation can in most cases be predicted from sequence signatures.

Glycolate oxidase, a ‘TIM barrel’

‘Roll out the barrel’

• Number of strands (n) and shear number (S) define geometry of β-barrels.

• Simple if S/n integral – then residues segregate into layers

• ‘Periodic table’ of β-barrels based on S and n

• (For serine proteinases, n = 6 and S = 8; 8/6 is NOT integral; what happens is quite an interesting story.)

‘TIM barrel’

Final comment :

I have another sabbatical coming up …