Discovery of low-molecular-weight ligands for the AF6 PDZ domain.
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Ligands↗
Biomedical subjects
Markus Schade
Publications and source records attributed to Markus Schade.
NMR fragment screening: Advantages and applications.
Nuclear magnetic resonance (NMR)-fragment-screening is a useful tool for lead identification and optimization in cases where shallow binding pockets have to be targeted, where highly selective lead structures are to be designed, and where novel, best-fit scaffolds for combinatorial library design are required. Robust and complementary protein- and ligand-detected NMR-screening methods are available for target proteins of various molecular weights and from different expression systems. The advantages of the NMR assay over other analytical techniques are high sensitivity toward loose fragment binders, comparatively high throughput and the ability to offer unique structural binding site information.
Drug Design↗
NMR fragment screening: tackling protein-protein interaction targets.
High-throughput screening of libraries containing compounds of 'drug-like' molecular weight has frequently resulted in no or poor drug candidates, especially when screening against demanding drug targets such as protein-protein interactions. Fragment-based lead discovery and optimization has evolved as a promising solution to this problem by combining the universal adaptability of low-molecular-weight fragments with immediate structural information on fragment binding modes. This review focuses on nuclear magnetic resonance (NMR) fragment screening techniques, which provide a unique combination of medium-throughput, direct binding site information and broad applicability. The utility and exemplary data of chemical shift-detected NMR fragment screening applied to the challenging protein-protein interaction target PDZ domains are summarized.
Animals↗
The solution structure of the N-terminal domain of E3L shows a tyrosine conformation that may explain its reduced affinity to Z-DNA in vitro.
The N-terminal domain of the vaccinia virus protein E3L (Z alpha(E3L)) is essential for full viral pathogenicity in mice. It has sequence similarity to the high-affinity human Z-DNA-binding domains Z alpha(ADAR1) and Z alpha(DLM1). Here, we report the solution structure of Z alpha(E3L) and the chemical shift map of its interaction surface with Z-DNA. The global structure and the Z-DNA interaction surface of Z alpha(E3L) are very similar to the high-affinity Z-DNA-binding domains Z alpha(ADAR1) and Z alpha(DLM1). However, the key Z-DNA contacting residue Y48 of Z alpha(E3L) adopts a different side chain conformation in unbound Z alpha(E3L), which requires rearrangement for binding to Z-DNA. This difference suggests a molecular basis for the significantly lower in vitro affinity of Z alpha(E3L) to Z-DNA compared with its homologues.
Amino Acid Sequence↗