The kinesin motor proteins are critical for many cellular functions, including cell division, vesicle and organelle transport, and motility. As such, it is implicated in neurological and development disorders and is a potential target for cancer therapy. Kinesin motors consist of two identical ~960 amino-acid chains that contain an N-terminal globular motor domain, a central a-helical region, and a C-terminal tail that binds light chains, which mediate binding to the cargo. An ATP binding site on the motor domain is the source of ATPase activity, which is used to convert chemical energy into mechanical motion. Kinesin walks along microtubules processively, where the motor domains make alternate contact with the microtubules. There are many questions related to the function of individual members of these families of proteins that could be answered if there existed specific membrane permeant small molecule inhibitors. Outside of nucleotide analogs, which are nonspecific, only a few molecules exist that specifically inhibit motor proteins at low concentrations. Adociasulfate-2 (AS-2) from the Haliclona sp. sea sponge inhibits microtubule-stimulated kinesin ATPase activity (IC50 = 2.7 μmM). Through computational and biochemical studies of AS-2 and kinesin, my laboratory has developed an understanding of how AS-2 inhibits the ATPase activity of kinesin. AS-2 does not behave as a classic 1:1 inhibitor of kinesin ATPase activity. Instead, the inhibitory entity is a rod-shaped aggregate that mimics microtubules. This is interesting because AS-2, as a chiral compound with multiple stereocenters, is an unusual type of aggregator, and its inhibitory action is contrary to assumptions made in the literature on its effects. The ordered structure of the aggregates is atypical. It is the first demonstration that a natural product can act as a “promiscuous” inhibitor through aggregation and an example of how a small molecule can disrupt a protein-protein interaction (kinesin-MT). It suggests that aggregates of small molecules might have interesting and biologically relevant properties.
The Survey on Doctoral Education and Career Preparation was a Pew Charitable Trusts-supported research project that sought to better understand the process of doctoral education from the perspective of graduate students. My collaborator, Chris Golde, and I surveyed 4114 doctoral students in 11 arts and sciences disciplines (including chemistry) at 28 programs across the US in order to understand why doctoral students pursue the Ph.D., how effective doctoral programs are at preparing students for academic and other careers, and how clear the process of doctoral education is to students before and during their course of study. The results of the survey, commonly referred to as the “Golde-Dore study,” were published in January 2001 (http://www.phd-survey.org) and a book chapter followed in 2004. The impact of the study was extraordinary. Numerous articles about it have appeared in scholarly, professional, and mass media, and the data have been used for a number of follow-up studies. The initial report has been downloaded from the study website over 19,000 times, and the data and findings have been used to improve doctoral programs worldwide.