Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin

Hanske, Jonas; Aleksić, Stevan; Ballaschk, Martin; Jurk, Marcel; Shanina, Elena; Beerbaum, Monika; Schmieder, Peter; Keller, Bettina G.; Rademacher, Christoph

doi:10.1021/jacs.6b05458

Cited by 39 publications

(96 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These structurala djustments for the p-hydroxymethylenebenzylamide arm illustratet he plasticityo ft he CRD backboneo fD C-SIGN as previously observed for langerin. [13] In the crystal, 16 interacts similarly to the previously characterizedb inding mode fort he glycomimetics 1-3 [3,14] exploiting Val351 side chain for nonpolari nteractions with the cyclohexane ring. Here, for the first time, details of the interaction of the benzylamide arm with the primary CRD surface, previously suggested by NMR studies, are highlighted.…”

Section: X-ray Crystallographymentioning

confidence: 85%

Enhancing Potency and Selectivity of a DC‐SIGN Glycomimetic Ligand by Fragment‐Based Design: Structural Basis

Medve

Achilli

Guzmán-Caldentey

et al. 2019

Chemistry A European J

View full text Add to dashboard Cite

Chemical modification of pseudo‐dimannoside ligands guided by fragment‐based design allowed for the exploitation of an ammonium‐binding region in the vicinity of the mannose‐binding site of DC‐SIGN, leading to the synthesis of a glycomimetic antagonist (compound 16) of unprecedented affinity and selectivity against the related lectin langerin. Here, the computational design of pseudo‐dimannoside derivatives as DC‐SIGN ligands, their synthesis, their evaluation as DC‐SIGN selective antagonists, the biophysical characterization of the DC‐SIGN/16 complex, and the structural basis for the ligand activity are presented. On the way to the characterization of this ligand, an unusual bridging interaction within the crystals shed light on the plasticity and potential secondary binding sites within the DC‐SIGN carbohydrate recognition domain.

show abstract

Section: X-ray Crystallographymentioning

confidence: 85%

Enhancing Potency and Selectivity of a DC‐SIGN Glycomimetic Ligand by Fragment‐Based Design: Structural Basis

Medve

Achilli

Guzmán-Caldentey

et al. 2019

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…Interestingly,m annose as well as most fragments also altered resonances of residues distant from their assigned primary pocket. [21] Theactivation of such an allosteric network might propagate via the neck domain, which could explain the signaling initiated by monovalent ligands. These long-distant perturbations might be caused by an allosteric network, which we recently identified to regulate Ca 2+ binding and release in the related CLR langerin.…”

mentioning

confidence: 99%

Identification of Multiple Druggable Secondary Sites by Fragment Screening against DC‐SIGN

et al. 2017

Self Cite

View full text Add to dashboard Cite

DC-SIGN is a cell-surface receptor for several pathogenic threats, such as HIV, Ebola virus, or Mycobacterium tuberculosis. Multiple attempts to develop inhibitors of the underlying carbohydrate-protein interactions have been undertaken in the past fifteen years. Still, drug-like DC-SIGN ligands are sparse, which is most likely due to its hydrophilic, solvent-exposed carbohydrate-binding site. Herein, we report on a parallel fragment screening against DC-SIGN applying SPR and a reporter displacement assay, which complements previous screenings using F NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and H- N HSQC NMR spectroscopy revealed that although no fragment bound in the primary carbohydrate site, five secondary sites are available to harbor drug-like molecules. Building on key interactions of the reported fragment hits, these pockets will be targeted in future approaches to accelerate the development of DC-SIGN inhibitors.

show abstract

“…that the protonation state can influence the extent and nature of the breathing motion, might still be valid. Such a role of histidine residues would not be unprecedented as a recent study suggested the protonation state of a His side chain can modulate loop flexibility and ligand release in Langerin, a C-type lectin receptor35.…”

Section: Resultsmentioning

confidence: 99%

Fine-tuning the extent and dynamics of binding cleft opening as a potential general regulatory mechanism in parvulin-type peptidyl prolyl isomerases

Czajlik

Kovács

Permi

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Parvulins or rotamases form a distinct group within peptidyl prolyl cis-trans isomerases. Their exact mode of action as well as the role of conserved residues in the family are still not unambiguously resolved. Using backbone S2 order parameters and NOEs as restraints, we have generated dynamic structural ensembles of three distinct parvulins, SaPrsA, TbPin1 and CsPinA. The resulting ensembles are in good agreement with the experimental data but reveal important differences between the three enzymes. The largest difference can be attributed to the extent of the opening of the substrate binding cleft, along which motional mode the three molecules occupy distinct regions. Comparison with a wide range of other available parvulin structures highlights structural divergence along the bottom of the binding cleft acting as a hinge during the opening-closing motion. In the prototype WW-domain containing parvulin, Pin1, this region is also important in forming contacts with the WW domain known to modulate enzymatic activity of the catalytic domain. We hypothesize that modulation of the extent and dynamics of the identified ‘breathing motion’ might be one of the factors responsible for functional differences in the distinct parvulin subfamilies.

show abstract

Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin

Cited by 39 publications

References 62 publications

Enhancing Potency and Selectivity of a DC‐SIGN Glycomimetic Ligand by Fragment‐Based Design: Structural Basis

Enhancing Potency and Selectivity of a DC‐SIGN Glycomimetic Ligand by Fragment‐Based Design: Structural Basis

Identification of Multiple Druggable Secondary Sites by Fragment Screening against DC‐SIGN

Fine-tuning the extent and dynamics of binding cleft opening as a potential general regulatory mechanism in parvulin-type peptidyl prolyl isomerases

Contact Info

Product

Resources

About