A Protein Structure (or Function ?) Initiative.

Departments of Biochemistry and Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue,Urbana, IL 61801, USA*Correspondence: j-gerlt@uiuc.eduDOI 10.1016/j.str.2007.10.003As a mechanistic enzymologist, myperspective on the Protein StructureInitiative (PSI) may be somewhat dif-ferent than those of many readersof Structure. I do not consider a highresolution structure as the end to aresearch problem but, instead, thebeginning that allows the formulationof structure-based hypotheses for en-zyme mechanisms and experimentalstrategies for elucidation of both thechemicalandstructuralbasesofthosemechanisms. Indeed, for much of mycareer I have enjoyed productive col-laborations with X-ray crystallogra-phers that always provided interestinginsights into structure-function rela-tionships for a variety of enzyme-cata-lyzed reactions.I admit to having been a discon-nected observer when PSI-1 was initi-ated. Those early stages of the PSIdid little to impact the direction of myscience, although I did wonder exactlyhow the inﬂux of structures that even-tually would emerge could impact myviews on and approaches to enzymol-ogy. I was aware of and perhaps evensympathetic to criticisms that struc-tures would be available for manyhighly divergent proteins of unknownfunction, but with no obvious way toput them to use. I was reminded of myearly, short-sighted views of genomesequencing in which I questioned thewisdom of robotic sequencing of vaststretches of DNA.But, with the passage of a few yearsandthecontinuedevolutionofmyownresearchinterests,Ihavecometoreal-ize that the biological, even the enzy-mological, landscape has changedsigniﬁcantly.Morethansixhundredge-nomes later, unanticipated complex-ities in both biology and enzymologyhave become apparent. We all havecome to appreciate that an unexpect-edlysmallnumberofgenesenablesthecomplexities of human biology, chal-lengingsimpleviewsofbiologicalfunc-tion. We also have learned of the im-portance of lateral gene transfer, evenbetween prokaryotes and eukaryotes,and that its role in the acquisition ofadaptive advantage is far more wide-spread than we could have expected.And, even in my own niche in mecha-nistic enzymology, we have come toappreciate that the creation of ‘‘new’’enzymatic functions by divergent evo-lution from ancestral proteins is ex-ceedingly widespread.Pointmutationsandsubsequentse-lective pressure can produce changesin substrate speciﬁcity while retaininga common chemical mechanism. Thedivergent members of such super-families (e.g., chymotrypsin, trypsin,elastase, and their homologs) canbe termed ‘‘speciﬁcity diverse’’ (GerltandBabbitt,2001).But,divergentevo-lutionalso canproducechanges intheoverall reactions that are catalyzedwhile retaining a partial chemical re-action (mechanistically diverse en-zyme superfamilies). Perhaps evenmore surprising, divergent evolutionfromacommonprogenitorcanproduceenzymes that share neither substratespeciﬁcitiesnorchemicalmechanisms(mechanistically distinct enzyme su-prafamilies). In retrospect, the forma-tion of enzyme superfamilies andsuprafamilies reﬂects the structuraladaptability of a relatively small num-ber of folds to catalyze an amazinglydiverse range of chemistry. For exam-ple, the (b/a)