Biomedical subjects

Yuanhong Li

Publications and source records attributed to Yuanhong Li.

4 recordsLinked to original sources

PubMed2006

Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design.

ZipA is a membrane anchored protein in Escherichia coli that interacts with FtsZ, a homolog of eukaryotic tubulins, forming a septal ring structure that mediates bacterial cell division. Thus, the ZipA/FtsZ protein-protein interaction is a potential target for an antibacterial agent. We report here an NMR-based fragment screening approach which identified several hits that bind to the C-terminal region of ZipA. The screen was performed by 1H-15N HSQC experiments on a library of 825 fragments that are small, lead-like, and highly soluble. Seven hits were identified, and the binding mode of the best one was revealed in the X-ray crystal structure. Similar to the ZipA/FtsZ contacts, the driving force in the binding of the small molecule ligands to ZipA is achieved through hydrophobic interactions. Analogs of this hit were also evaluated by NMR and X-ray crystal structures of these analogs with ZipA were obtained, providing structural information to help guide the medicinal chemistry efforts.

Anti-Bacterial Agents↗

PubMed2005

Classifiability-based omnivariate decision trees.

Top-down induction of decision trees is a simple and powerful method of pattern classification. In a decision tree, each node partitions the available patterns into two or more sets. New nodes are created to handle each of the resulting partitions and the process continues. A node is considered terminal if it satisfies some stopping criteria (for example, purity, i.e., all patterns at the node are from a single class). Decision trees may be univariate, linear multivariate, or nonlinear multivariate depending on whether a single attribute, a linear function of all the attributes, or a nonlinear function of all the attributes is used for the partitioning at each node of the decision tree. Though nonlinear multivariate decision trees are the most powerful, they are more susceptible to the risks of overfitting. In this paper, we propose to perform model selection at each decision node to build omnivariate decision trees. The model selection is done using a novel classifiability measure that captures the possible sources of misclassification with relative ease and is able to accurately reflect the complexity of the subproblem at each node. The proposed approach is fast and does not suffer from as high a computational burden as that incurred by typical model selection algorithms. Empirical results over 26 data sets indicate that our approach is faster and achieves better classification accuracy compared to statistical model select algorithms.

Algorithms↗

PubMed2004

Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA-FtsZ interaction.

The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA-FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding. The X-ray crystal structure of one of these molecules complexed with ZipA was solved. The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.

Amino Acid Sequence↗

PubMed2002

Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis.

Chromosomal translocations involving the human CBFB gene, which codes for the non-DNA binding subunit of CBF (CBF beta), are associated with a large percentage of human leukemias. The translocation inv(16) that disrupts the CBFB gene produces a chimeric protein composed of the heterodimerization domain of CBF beta fused to the C-terminal coiled-coil domain from smooth muscle myosin heavy chain (CBF beta-SMMHC). Isothermal titration calorimetry results show that this fusion protein binds the Runt domain from Runx1 (CBF alpha) with higher affinity than the native CBF beta protein. NMR studies identify interactions in the CBF beta portion of the molecule, as well as the SMMHC coiled-coil domain. This higher affinity provides an explanation for the dominant negative phenotype associated with a knock-in of the CBFB-MYH11 gene and also helps to provide a rationale for the leukemia-associated dysregulation of hematopoietic development that this protein causes.

Amino Acid Sequence↗