Robert Stroud

Research Interests

Structure & function of (macromolecules) high resolution structures of protein, especially membrane proteins.

Research Summary

Please see http://msg.ucsf.edu/stroud/index.htm for a current summary. Focus is on understanding how macromolecular structure encodes specificity and affinity in biology, and how this can be used for drug design. Toward this goal we have solved the high resolution x-ray structures of nineteen different paradigms that define mechanisms.

Recent active areas of research:
Inhibitor designs, Enzyme mechanisms: Drug design efforts focus an important anti-cancer drug target, thymidylate synthase We target human TS and TS from several pathogens that affect immune compromised persons and AIDS. The goal is to design species specific anti TS drugs. Several combinatorial methods are aimed at this critically important target alongside the structure based approach. AIDS opportunistic infectives include Pneumocystis carinii, Cryptococcus, Cryptosporidium and Toxoplasma. New principles are being developed that will lead to iterative improvement in the computer design of selectivity of new inhibitors, lead compounds, and drugs.
HIV-1 integrase is a second major target for our structure based drug development program. We are working in concert with the biological group of Andy Leavitt, Tack Kuntz and the organic synthesis group of Paul Ortiz de Montellano to determine the structure of integrase with inhibitors bound. In protein design
we seek to design novel protein catalytic function into a de novo designed protein.
Signal Recognition Particle: Signal sequences which target proteins for secretion or for membrane are recognized specifically by the signal recognition particle (SRP). The structure reveals a deep groove lined with hydrophobic and a highly conserved, arginine-rich motif that binds to SRP RNA.
Transmembrane Signaling: We study the transmembrane channels formed by neuroreceptors, including transporters, and the acetylcholine receptor, and analogs of component portions that define ligand binding, and channel formation.
Membrane channel proteins of the aquaporin family are highly selective for permeation of specific small molecules, with absolute exclution of ions and charged solutes, and without dissipating the electromechanical potential across the cell membrane. We have determined the structure at 2.2 A resolution of an integral transmembrane channel (GlpF), with its primary permeant substrate glycerol. This structure elucidates the mechanism of selective permeability for linear carbohydrates and suggests how ions and water are excluded. Molecular mechanics is used to understand and predict conductance and selectivity of channels along side function and structure.

Selected Publications

Scientific Publications:

Stroud, R.M., and Finer-Moore, J.S. (2003). Biochemistry 42, 239-247. Conformational dynamics along an enzymatic reaction pathway: thymidylate synthase, "the Movie"Savage, D. F., Egea, P.F., Robles, Y.C., O'Connell III, J.D., and Stroud, R.M. (2003) PLoS Biology 1, 334-340. [with Journal Cover, and Synopsis 1 302.] Architecture and selectivity in aquaporins: 2.5 X-ray structure of aquaporin Z

Keatinge-Clay A.T., Shelat A.A., Savage D.F., Tsai S.C., Miercke L.J., O'Connell, J., Khosla, C., and Stroud, R.M. (2003). Structure (Camb) 11, 147-154. Catalysis, specificity, and ACP docking site of Streptomyces coelicolor malonyl-CoA:ACP transacylase.

Egea, P.F., Shan, S.O., Napetschnig, J., Savage, D.F., Walter, P., and Stroud, R.M. (2004) Nature 426, 215-221. Substrate twinning activates the signal recognition particle and its receptor

The Channel Architecture of Aquaporin 0 At 2.2 n Resolution. Harries, W.E.C., Akhavan, D., Miercke, L.J.W., Khademi, S., Stroud, R.M. Proc Nat Acad Sci 101, 14045-14050

Khademi, S., O'Connell III, J., Remis, J., Robles-Colmenares, Y., Miercke L.J.W., Stroud, R.M. (2004) Science 305, 1587-1594. [Cover Article, with Perspective by Knepper and Agre p1573-1574.] Mechanism of Ammonia Transport by Amt/MEP/Rh: Structure of AmtB at 1.35