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Small Molecule-Induced Proximity

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Chembiomolecular Science

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Abstract

Every cell in a living organism is like a tiny chemical reaction vessel. Although the cell is far smaller in size than a typical chemical reaction flask, the complexity of the reactions is remarkable and highly coordinated. A typical chemical reaction in the laboratory usually has a few well-defined chemical reactants; in contrast, there are millions of different biological molecules coexisting at any moment in a cell. How does the cell control the selectivity of interactions between two or a few biomolecules among the seas of others? To solve this problem, Nature evolved delicate mechanisms to control the proximity between cellular molecules to regulate their interactions. In a laboratory chemical reaction, chemical reactants are often mixed together in micromolar to molar (μM to M) concentrations. Such a high concentration is used to facilitate the chemical reaction. However, under such conditions, the reactive functional moieties in each molecule have to be carefully designed and manipulated to prevent unwanted side reactions. In a cell, however, most of the biological molecules typically exist in nanomolar to micromolar (nM to μM) concentrations. In such a low concentration, the chance of efficient interactions between biomolecules is very low unless assisted by special cellular mechanisms to bring specific biomolecules into proximity to promote their interactions; for example, the dimerization of receptor tyrosine kinases in the presence of extracellular stimuli to trigger intracellular signaling [1], or the synthesis of proteins using mRNA as templates and dedicated cellular machineries to bring correct building blocks in order into proximity to produce proteins with accurate sequences. In fact, many protein domains have evolved to mediate the proximity between different biomolecules. For example, the SH2 domain recognizes the phosphotyrosine residue, the bromo or the PHD domain recognizes acetylated or methylated histone tails, the PAZ domain binds the 3′-overhangs of small interfering (si)RNA, or a DNA-binding domain recognizes a specific DNA sequence. These recognition domains direct individual catalytic or effective domains to specific action locations and regulate downstream cellular processes. Nature uses such proximity control in combination with allostery and other mechanism to regulate complex arrays of biological events [2].

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Beckman Center B211, Stanford University School of Medicine, 5323, 279 Campus Drive, Stanford, CA, 94305-5323, USA

    Fu-Sen Liang & Gerald R. Crabtree

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  1. Fu-Sen Liang
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  2. Gerald R. Crabtree
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Correspondence to Gerald R. Crabtree .

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Editors and Affiliations

  1. Institute of Microbial Chemistry, Kamioosaki 3-14-23, Tokyo, 141-0021, Japan

    Masakatsu Shibasaki

  2. The University of Tokyo, Department of Pharmacology, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, 113-0033, Japan

    Masamitsu Iino

  3. RIKEN Advanced Science Institute, Antibiotics Laboratory, Chemical Biology Core Facility, 2-1, Hirosawa, Wako, 351-0198, Saitama, Japan

    Hiroyuki Osada

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Liang, FS., Crabtree, G.R. (2012). Small Molecule-Induced Proximity. In: Shibasaki, M., Iino, M., Osada, H. (eds) Chembiomolecular Science. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54038-0_11

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