Biophysical Reviews

, Volume 10, Issue 2, pp 421–433 | Cite as

“Multiple partial recognitions in dynamic equilibrium” in the binding sites of proteins form the molecular basis of promiscuous recognition of structurally diverse ligands

  • Daisuke Kohda


Promiscuous recognition of ligands by proteins is as important as strict recognition in numerous biological processes. In living cells, many short, linear amino acid motifs function as targeting signals in proteins to specify the final destination of the protein transport. In general, the target signal is defined by a consensus sequence containing wild-characters, and hence represented by diverse amino acid sequences. The classical lock-and-key or induced-fit/conformational selection mechanism may not cover all aspects of the promiscuous recognition. On the basis of our crystallographic and NMR studies on the mitochondrial Tom20 protein–presequence interaction, we proposed a new hypothetical mechanism based on “a rapid equilibrium of multiple states with partial recognitions”. This dynamic, multiple recognition mode enables the Tom20 receptor to recognize diverse mitochondrial presequences with nearly equal affinities. The plant Tom20 is evolutionally unrelated to the animal Tom20 in our study, but is a functional homolog of the animal/fungal Tom20. NMR studies by another research group revealed that the presequence binding by the plant Tom20 was not fully explained by simple interaction modes, suggesting the presence of a similar dynamic, multiple recognition mode. Circumstantial evidence also suggested that similar dynamic mechanisms may be applicable to other promiscuous recognitions of signal peptides by the SRP54/Ffh and SecA proteins.


Mitochondrial presequence Promiscuous recognition Signal sequence Targeting signal Tom20 



Endoplasmic reticulum


Molecular dynamics


Multiple partial recognition in dynamic equilibrium


Nuclear Overhauser effect


Translocase of the inner mitochondrial membrane


Translocase of the outer mitochondrial membrane


20-kDa subunit of the TOM complex


Paramagnetic relaxation enhancement



This review is the achievement of our long-term research project for more than 20 years, conducted at the Biomolecular Engineering Research Institute with Drs. Yoshito Abe and Takanori Muto, and at the Medical Institute of Bioregulation, Kyushu University, with Drs. Takayuki Obita, Takashi Saitoh, Toyoyuki Ose, Nobuo Maita, Reiko Kojima, Mayumi Igura, Rei Matsuoka, and Atsushi Shimada, Mr. Keisei Izumi, and Ms. Han Xiling. We thank Professor Toshiya Endo (Kyoto Sangyo University) for fruitful discussions on the biochemical functions of the TOM and TIM proteins, and Drs. Yasuaki Komuro and Yuji Sugita (RIKEN Advanced Science Institute), and Dr. Naoyuki Miyashita (RIKEN Quantitative Biology Center) for their MD calculations and stimulating discussions.

Compliance with ethical standards

Conflict of interest

Daisuke Kohda declares that the author has no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.


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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Division of Structural Biology, Medical Institute of BioregulationKyushu UniversityFukuokaJapan

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