I vividly remember when I decided to become a structural biologist. The epiphany occurred when, for a university assignment, I came across the revolutionary work of Kohlstaedt et al., published in Science in 1992. This paper reports the structure of the human immunodeficiency virus 1 reverse transcriptase (HIV-1 RT). For the first time, the enzyme performing the crucial ‘reverse transcription’ of the viral RNA genome into DNA was visualized at atomic resolution. HIV-1 RT is composed of two proteins, p66 and p51, arranged in a ‘hand’ shape, into which the RNA is accommodated to be replicated into DNA.

This work was a real game-changer, because it revealed the binding pocket of nevirapine, a drug that had shown promise in improving the survival of individuals with AIDS. Nevirapine throws sand in the gears of the reverse-ranscription machinery by binding to p61 outside of its RNA-binding surface, thereby preventing the enzyme from correctly ‘grabbing’ the RNA. Importantly, the binding site of nevirapine lies in a conserved region of HIV-1 RT, so the notoriously mutating virus is unlikely to develop resistance to it, a cause that is responsible for the loss of efficacy of other treatments.

The structure of HIV-1 RT paved the way to the development of a class of drugs that, 28 years later, are still used to treat HIV. According to the World Health Organization, the work of Kohlstaedt et al. contributed to saving the lives of almost 26 million people (see who.int/gho/hiv/epidemic_response/ART/en/) as well as to reducing the stigma associated with contracting HIV and with AIDS, which I had witnessed growing up in the 1990s.

According to the World Health Organization, the work of Kohlstaedt et al. contributed to saving the lives of almost 26 million people

Kohlstaedt’s work imparted two valuable lessons to me. It has taught me that a protein structure can have great medical potential, and that treatments can be found for the most vicious viruses, sometimes by looking in unanticipated places. These lessons represent an inspiration in the current, bizarre times of the COVID-19 pandemic.