A close and productive collaboration with the laboratory of Dr. Barry Coller at Rockefeller University has kept part of our research interests focused on the study of structure-function relationships of both aIIbb3 and aVb3 integrins. The lab’s interest in these systems stems from the exciting computational challenges they pose, and the opportunity to develop and/or apply cutting-edge computational approaches that will render accurate representations of the dynamic allosteric mechanisms regulating integrin function.
During the past 15 years we have been able to provide an innovative structure-guided approach to the functional studies carried out in the lab of our experimental collaborator. Specifically, we have contributed i) Early three-dimensional molecular models of aIIbb3 using aVb3 as a template; ii) Important structural insights into the ligand-associated metal binding site (LIMBS, later re-termed SyMBS) of β3 integrins from molecular dynamics (MD) simulations; iii) Specific molecular determinants for limiting extension at the αIIb genu or ligand binding to integrin αIIbβ3; iv) Information about the overall common conformational changes occurring in β3 integrins upon hybrid domain swing-out using targeted MD simulations; v) Mechanistic information about αIIbβ3- and αVβ3-specific antagonists that stabilize the receptors in their resting states, vi) Structure-guided design of potent pure antagonist of β3 receptors; vii) Identification of novel antagonists by virtual screening, viii) Multimicrosecond, all-atom MD simulations of the talin-driven inside-out activation mechanism of αIIbβ3 integrin, and ix) Predictions of the functional effect of αIIbβ3 variants defined by next-generation sequencing.
Zhu, J., Zhu, J., Negri, A., Provasi, D., Filizola, M., Coller, B.S., Springer, T.A. “Closed headpiece of integrin αIIbβ3 and its complex with an αIIbβ3-specific antagonist that does not induce opening” Blood (2010) 116 (23):5050-5059.
Negri, A., Li, J., Naini, S., Coller, B.S., Filizola, M. “Structure-Based Virtual Screening of Small-Molecule Antagonists of Platelet Integrin αIIbβ3that Do Not Prime the Receptor to Bind Ligand” Journal of Computer-Aided Molecular Design (2012) 26 (9): 1005-1015
Zhu, J., Choi, W.-S., McCoy, J. G., Negri, A., Zhu, J., Naini, S., Li, J., Shen, M., Huang, W., Bougie, D., Rasmussen, M., Aster, R., Thomas, C. J., Filizola, M., Springer, T. A., Coller, B. S. “Structure-Guided Design of a High-Affinity Platelet Integrin αIIbβ3Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS.” Science Translational Medicine (2012) 4: 125ra32
Buitrago, L., Rendon, A., Liang, Y., Turro, E., Simeoni, I., Negri, A., ThromboGenomics Consortium, Filizola, M., Ouwehand, W.H., Coller, B.S. “αIIbβ3 Variants Defined by Next Generation Sequencing: Predicting Variants Likely to Cause Glanzmann Thrombasthenia” (2015)Proceedings of the National Academy of Science USA, 112(15):E1898-907.