Foci of amino acid residue conservation in the 3D structures of the Kunitz BPTI proteinase inhibitors: how do variants from snake venom differ?
The Kunitz BPTI proteinase inhibitor family is divisible into subgroups based on source and bioactivity. Variants from snake venoms are of special interest because some show only weak inhibitory activity against the common proteinases while others are neurotoxic. We analysed the sequences for each subgrouping in the context of the common chain fold to predict the 3D location of interactive sites. The method used was an enhanced from of the previously devised 'regiovariation analysis.' This revealed the foci in 3D of amino acid side chain conservation in each subgroup. Locally high levels of side-chain conservation extending substantially in three dimensions can be associated more with the preservation of function than conformation, hence the foci probably reveal the most functionally relevant sites. For the inhibitor variants that do not originate from snake venom, regiovariation analysis gave an exact prediction of the antiproteinase site revealed by X-ray crystallography of inhibitor-enzyme complexes. However, this site is not the principal focus of evolutionary conservation in the inhibitors from snake venom, and other areas of the molecular surface are more prominent. The neurotoxic variants from snake venom (the dendrotoxins) have the principal focus of conservation near their C-terminal region, so this may be the origin of their special properties.
Cardle
L
L
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, U.K.
Dufton
M J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D007611:Aprotinin / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D002038:Bungarotoxins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D002417:Cattle; D017124:Conserved Sequence; D004546:Elapid Venoms / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D019143:Evolution, Molecular; D014644:Genetic Variation; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D015202:Protein Engineering; D012910:Snake Venoms / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity
D002038:Bungarotoxins; D004546:Elapid Venoms; D012910:Snake Venoms; C020273:dendrotoxin; D007611:Aprotinin