A systematic analysis of atomic protein–ligand interactions in the PDB

Freitas, Renato Ferreira de; Schapira, Matthieu

doi:10.1039/c7md00381a

Cited by 338 publications

(289 citation statements)

References 115 publications

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“…This interaction may also contribute to improved PBD-binding since contacts involving leucine residues are among the most frequent hydrophobic interactions observed in protein-ligand complexes. 32 …”

Section: X-ray Co-crystal Studiesmentioning

confidence: 99%

Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors

Hymel

Grant

Tsuji

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLHSpT (2a) (where H indicates the presence of a -(CH)Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. The resulting macrocycles are highly potent in biochemical assays and maintain good target selectivity for the Plk1 PBD versus the PBDs of Plk2 and Plk3. Importantly, as exemplified by 5d, our current approach permits deletion of the N-terminal "Pro-Leu" motif to yield tripeptide ligands with decreased molecular weight, which retain high affinity and show improved target selectivity. These findings could fundamentally impact the future development of peptide macrocycles in general and Plk1 PBD-binding peptide mimetics in particular.

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Section: X-ray Co-crystal Studiesmentioning

confidence: 99%

Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors

Hymel

Grant

Tsuji

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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“…[6] However,this effect is applied to synthetic molecular recognition [7] and is also common in biological assemblies. [8] Herein, we report an ew molecular tube-based ternary complex with as trong positive cooperativity (a = 580). This is achieved by "waking up" relatively weak CÀH···O hydrogen bonds between two molecular tubes in the complex.…”

mentioning

confidence: 99%

“…Thec omplex was further applied to construct ar obust [2+ +2] cyclic complex, demonstrating its potential as ab inding motif for the construction of large supramolecular architectures.T he present research showcases that relatively weak non-covalent interactions may result in strong positive cooperativity,w hich is often the feature of biological assemblies. [8,20]…”

mentioning

confidence: 99%

Achieving Strong Positive Cooperativity through Activating Weak Non‐Covalent Interactions

Valkonen

et al. 2017

Angew Chem Int Ed

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Positive cooperativity achieved through activating weak non-covalent interactions is common in biological assemblies but is rarely observed in synthetic complexes. Two new molecular tubes have been synthesized and the syn isomer binds DABCO-based organic cations with high orientational selectivity. Surprisingly, the ternary complex with two hosts and one guest shows a high cooperativity factor (α=580), which is the highest reported for synthetic systems without involving ion-pairing interactions. The X-ray single-crystal structure revealed that the strong positive cooperativity likely originates from eight C-H⋅⋅⋅O hydrogen bonds between the two head-to-head-arranged syn tube molecules. These relatively weak hydrogen bonds were not observed in the free hosts and only emerged in the complex. Furthermore, this complex was used as a basic motif to construct a robust [2+2] cyclic assembly, thus demonstrating its potential in molecular self-assembly.

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“…Among the glucose molecules substituted at the 4 and 6 positions, 85/83 and 92/93 % of the α/β variants have one or more HBs with the bridging water molecules. On average, α/β‐glucose and α/β‐galactose molecules have 1.8/1.8 and 2.5/1.6 HBs with the bridging water molecules, whereas an average over all PDB ligands is 0.4 HB . These numbers increase for the substituted molecules to 3.2/3.4 for α/β‐glucose substituted on the 4 position and 4.1/2.9 for α/β‐glucose substituted on the 6 position.…”

Section: Resultsmentioning

confidence: 97%

“…On average, a/b-glucose and a/bgalactose molecules have 1.8/1.8 and 2.5/1.6 HBs with the bridging water molecules, whereas an average over all PDB ligands is 0.4 HB. [45] These numbersi ncreasef or the substituted molecules to 3.2/3.4 for a/b-glucose substituted on the 4p osition and 4.1/2.9 for a/b-glucose substituted on the 6p osition. For ar esolution 2 ,a ll the sugar molecules tend to have more HBs with the water:o na verage, a/b-glucose and a/bgalactose molecules have 2.3/2.2 and 2.9/1.8 HBs with the bridging water molecules.…”

Section: Pdb-wide Analysis Of Hydrogen Bondsatthe Interface Of Proteimentioning

confidence: 95%

The Role of Bridging Water and Hydrogen Bonding as Key Determinants of Noncovalent Protein–Carbohydrate Recognition

Ruvinsky

Aloni

Cappel³

et al. 2018

ChemMedChem

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Mechanisms of protein–carbohydrate recognition attract a lot of interest due to their roles in various cellular processes and metabolism disorders. We have performed a large‐scale analysis of protein structures solved in complex with glucose, galactose and their substituted analogues. We found that, on average, sugar molecules establish five hydrogen bonds (HBs) in the binding site, including one to three HBs with bridging water molecules. The free energy contribution of bridging and direct HBs was estimated using the free energy perturbation (FEP+) methodology for mono‐ and disaccharides that bind to l‐ABP, ttGBP, TrmB, hGalectin‐1 and hGalectin‐3. We show that removing hydroxy groups that are engaged in direct HBs with the charged groups of Asp, Arg and Glu residues, protein backbone amide or buried water dramatically decreases binding affinity. In contrast, all solvent‐exposed hydroxy groups and hydroxy groups engaged in HBs with the solvent‐exposed bridging water molecules contribute weakly to binding affinity and so can be replaced to optimize ligand potency. Finally, we rationalize an effect of binding site water replacement on the binding affinity to l‐ABP.

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A systematic analysis of atomic protein–ligand interactions in the PDB

Cited by 338 publications

References 115 publications

Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors

Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors

Achieving Strong Positive Cooperativity through Activating Weak Non‐Covalent Interactions

The Role of Bridging Water and Hydrogen Bonding as Key Determinants of Noncovalent Protein–Carbohydrate Recognition

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