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Deciphering the kinetic binding mechanism of dimeric ligands, using a potent plasma-stable dimeric inhibitor of postsynaptic density protein-95 as an example

Chi, Celestine N., (författare)
Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, Per jemth
Bach, Anders, (författare)
University of Copenhagen
Gottschalk, Marie, (författare)
University of Copenhagen
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Kristensen, S. Anders, (författare)
University of Copenhagen
Strømgaard, Kristian, (författare)
University of Copenhagen
Jemth, Per, (författare)
Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:36, s. 28252-28260
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
  • <p>Dimeric ligands can be potent inhibitors of protein-protein or enzyme-substrate interactions. They have increased affinity and specificity towards their targets due to their ability to bind simultaneously to two binding sites and are therefore very attractive in drug design. However, few studies have addressed the kinetic mechanism of interaction of such bivalent ligands. We have investigated the binding interaction of a recently identified potent plasma-stable dimeric pentapeptide of PDZ1-2 of PSD-95 using protein engineering in combination with fluorescence polarisation, isothermal titration calorimetry and stopped-flow fluorimetry. Our experiments demonstrate that binding occurs via a two-step process, where an initial binding to either one of the two PDZ domains is followed by an intramolecular step, which produces the bidentate complex. We have determined all rate constants involved in the binding reaction and we also find evidence for a conformational transition of the complex. Our data demonstrate the importance of a slow dissociation for a successful dimeric ligand, but also highlight the possibility of optimizing the intramolecular association rate. The results may therefore aid the design of dimeric inhibitors in general.</p>


MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Annan medicinsk grundvetenskap (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Other Basic Medicine (hsv//eng)


protein-protein interactions
dimeric ligand
conformational change
MEDICINE Chemistry

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