How these molecular machines make life as we know it possible

Linus Pauling proposed transition state stabilization as the fundamental mechanism for enzyme catalysis in 1948. William Jencks quantified catalytic strategies contributing to rate enhancements. Biochemists measure enzyme proficiency—the ratio of catalyzed to uncatalyzed rates—ranging from 10^6 to 10^17-fold acceleration.

Northrop crystallized chymotrypsin in 1930s enabling structural studies. David Blow solved the three-dimensional structure revealing the catalytic mechanism in the 1960s. Biochemistry educators use chymotrypsin as canonical example teaching enzyme catalysis. Digestive physiologists study pancreatic protease secretion and activation.

Christian Anfinsen demonstrated that amino acid sequence determines three-dimensional structure through his ribonuclease refolding experiments earning the 1972 Nobel Prize. Structural biologists correlate protein structures with functions across protein families. Computational biologists predict function from structure using AlphaFold and related tools.

Irving Schechter and Arieh Berger developed nomenclature for protease substrate binding sites in 1967. Structural biologists map binding pockets explaining enzyme selectivity. Protein engineers redesign pockets altering substrate preferences for biotechnology applications. Drug designers target binding pockets creating selective competitive inhibitors.

David Blow and colleagues elucidated the serine protease catalytic triad mechanism through X-ray crystallography in the 1960s. Joseph Kraut determined subtilisin structure revealing convergent evolution of the same triad. Biochemists recognize the Ser-His-Asp triad as one of biology’s most elegant catalytic solutions.

Alexander Wlodawer and colleagues determined HIV protease structure in 1989. The enzyme became major antiretroviral drug target. Pharmaceutical researchers developed protease inhibitors transforming HIV from death sentence to manageable chronic condition. Virologists study protease’s role in viral maturation and drug resistance mutations.

Joseph Vacca led Merck’s team developing indinavir receiving FDA approval in 1996. Irving Sigal’s group determined HIV protease structure guiding rational design. Clinical researchers demonstrated indinavir’s efficacy in combination antiretroviral therapy dramatically reducing AIDS mortality. Structural biologists solved indinavir-protease complexes revealing atomic-detail binding.