Rational design to control the trade-off between receptor affinity and cooperativity.

Autor:	Ortega G; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106.; Center for Bioengineering, University of California, Santa Barbara, CA 93106., Mariottini D; Department of Chemistry, University of Rome Tor Vergata, 00173 Rome, Italy., Troina A; Department of Chemistry, University of Rome Tor Vergata, 00173 Rome, Italy., Dahlquist FW; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106.; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106., Ricci F; Department of Chemistry, University of Rome Tor Vergata, 00173 Rome, Italy., Plaxco KW; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106; kwp@chem.ucsb.edu.; Center for Bioengineering, University of California, Santa Barbara, CA 93106.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Aug 11; Vol. 117 (32), pp. 19136-19140. Date of Electronic Publication: 2020 Jul 29.
DOI:	10.1073/pnas.2006254117
Abstrakt:	Cooperativity enhances the responsiveness of biomolecular receptors to small changes in the concentration of their target ligand, albeit with a concomitant reduction in affinity. The binding midpoint of a two-site receptor with a Hill coefficient of 1.9, for example, must be at least 19 times higher than the dissociation constant of the higher affinity of its two binding sites. This trade-off can be overcome, however, by the extra binding energy provided by the addition of more binding sites, which can be used to achieve highly cooperative receptors that still retain high affinity. Exploring this experimentally, we have employed an "intrinsic disorder" mechanism to design two cooperative, three-binding-site receptors starting from a single-site-and thus noncooperative-doxorubicin-binding aptamer. The first receptor follows a binding energy landscape that partitions the energy provided by the additional binding event to favor affinity, achieving a Hill coefficient of 1.9 but affinity within a factor of 2 of the parent aptamer. The binding energy landscape of the second receptor, in contrast, partitions more of this energy toward cooperativity, achieving a Hill coefficient of 2.3, but at the cost of 4-fold poorer affinity than that of the parent aptamer. The switch between these two behaviors is driven primarily by the affinity of the receptors' second binding event, which serves as an allosteric "gatekeeper" defining the extent to which the system is weighted toward higher cooperativity or higher affinity. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu