Three main foci characterize my research. First, we aim to understand transport, cellular signaling and communication across cell membranes at the molecular level. Most recently this includes the first structures of channels in endolysosomes (TPCs) that participate in regulating nutrient acquisition. This gave us the first structure of any resting state voltage sensor, because its voltage sensitivity is tuned by lumenal calcium ions that lead to a ~1% open probability at 0 volts potential across the membrane. Most recently we removed this regulatory site, changing the open probability to ~99% at 0 volts. This gave us the first case of any voltage sensor seen in resting, and in active state in the same voltage gated ion channel. TPCs are critical to Ebola viral fusion and entry via the endolysosome; the structure is bound to an inhibitor NED19 that cures infected mice of Ebola. Another aim is on packaging of neurotransmitters into synaptic vesicles. The second focus is on understanding how macromolecular structure encodes specificity and affinity, at protein - protein and at protein - ligand interfaces, and how this can be used for biotherapeutics and drug design. To these ends we have determined the high-resolution three-dimensional atomic structures of over 330 proteins in many different classes, and used these structures to help define biological, biochemical, and cellular function, and as templates for drug design. We seek to determine the structures of membrane receptors, channels and transporters using X-ray and cryo electron microscopy. We address the cellular partners of HIV proteins in attempts to elucidate novel drug targets for anti-HIV therapy. We also address recently identified essential enzymes and transporters of mycobacterium tuberculosis, and P.falciparum as targets for drug discovery. The third area of focus concerns RNA-protein recognition, specificity and modification. We described and decoded several methylases, pseudouridine synthases showing how they achieve specificity by allosteric alteration of RNA. The most recent of these is the RNA methylase that tailors Lys3 tRNA by methylating the base A58; bases 58-72 act as the primer for HIV reverse transcription. Knockout of this enzyme reduces HIV viral infectivity by ~50%.