A5034171971- Enzyme Structure and Function
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Cancer Research and Treatments
- DNA and Nucleic Acid Chemistry
- Viral Infections and Outbreaks Research
- Protein Degradation and Inhibitors
- Amoebic Infections and Treatments
- Amino Acid Enzymes and Metabolism
- Drug Transport and Resistance Mechanisms
- Antibiotic Resistance in Bacteria
- Trace Elements in Health
- Lanthanide and Transition Metal Complexes
- Ubiquitin and proteasome pathways
- Mycobacterium research and diagnosis
- Bacterial Genetics and Biotechnology
- Cancer therapeutics and mechanisms
- Clostridium difficile and Clostridium perfringens research
- Epigenetics and DNA Methylation
- Iron Metabolism and Disorders
- RNA and protein synthesis mechanisms
- Tuberculosis Research and Epidemiology
- Hemoglobinopathies and Related Disorders
- Chemical Synthesis and Analysis
- Viral Infections and Vectors
Novartis (United States)
2023-2024
Nurix (United States)
2022-2024
North Seattle College
2024
Beryllium (United States)
2014-2022
Fred Hutch Cancer Center
2008-2019
Joint Center for Structural Genomics
2011-2017
Seattle University
2016
Purdue University West Lafayette
2014
Center for Infectious Disease Research
2013
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2011
The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness β-lactam class antimicrobials. A program was initiated to discover a new series serine β-lactamase inhibitors containing boronic acid pharmacophore, with goal finding potent inhibitor carbapenemase enzymes that are currently compromising utility carbapenem antibacterials. Potential lead structures were screened silico by modeling into active sites key β-lactamases. Promising...
Here, we report that lipocalin 2 (Lcn2) promotes breast cancer progression, and identify the mechanisms underlying this function. We first found Lcn2 levels were consistently associated with invasive in human tissue urine samples. To investigate function of was overexpressed cells to up-regulate mesenchymal markers, including vimentin fibronectin, down-regulate epithelial marker E-cadherin, significantly increase cell motility invasiveness. These changes expression are hallmarks an...
Malignant tumors can evade destruction by the immune system attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, deficiency reduces tumor growth mice. Here we report discovery NVP-DKY709, selective molecular glue degrader that spares IKZF1/3. We describe recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 redirected degradation selectivity cereblon...
Bruton's tyrosine kinase (BTK), a member of the TEC family kinases, is an essential effector B-cell receptor (BCR) signaling. Chronic activation BTK-mediated BCR signaling hallmark many hematological malignancies, which makes it attractive therapeutic target. Pharmacological inhibition BTK enzymatic function now well-proven strategy for treatment patients with these malignancies. We report discovery and characterization NX-2127, degrader concomitant immunomodulatory activity. By design,...
Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate complications and has been intently pursued. However, safe effective small-molecule inducers HbF remain elusive. We report the discovery dWIZ-1 dWIZ-2, molecular glue degraders WIZ transcription factor that robustly induce erythroblasts. Phenotypic screening cereblon (CRBN)-biased chemical library revealed as...
Antimicrobial proteins comprise a significant component of the acute innate immune response to infection. They are induced by pattern recognition receptors as well cytokines and adaptive pathways play important roles in infection control immunomodulatory homeostasis. Lipocalin 2 (siderocalin, NGAL, 24p3), siderophore-binding antimicrobial protein, is critical for systemic with Escherichia coli; however, its role mucosal immunity respiratory tract unknown. In this study, we found that...
The genus Burkholderia includes pathogenic gram-negative bacteria that cause melioidosis, glanders, and pulmonary infections of patients with cancer cystic fibrosis. Drug resistance has made development new antimicrobials critical. Many approaches to discovering antimicrobials, such as structure-based drug design whole cell phenotypic screens followed by lead refinement, require high-resolution structures proteins essential the parasite.We experimentally identified 406 putative genes in B....
The siderophore enterobactin (Ent) is produced by enteric bacteria to mediate iron uptake. Ent scavenges and taken up the as highly stable ferric complex [FeIII(Ent)]3−. This also a specific target of mammalian innate immune system protein, Siderocalin (Scn), which acts an antibacterial agent specifically sequestering siderophores their complexes during infection. Recent literature suggesting that Scn may be involved in cellular transport has increased importance understanding mechanism...
Siderocalin (also lipocalin 2, NGAL or 24p3) binds iron as complexes with specific siderophores, which are low molecular weight, ferric ion-specific chelators. In innate immunity, siderocalin slows the growth of infecting bacteria by sequestering bacterial siderophores. also simple catechols, can serve siderophores in damaged urinary tract. has been proposed to alter cellular trafficking, for instance, driving apoptosis through efflux via BOCT. An endogenous siderophore composed gentisic...
This paper describes the use of layer-by-layer growth metal−bis(phosphonate) multilayers to produce acentric thin films with second-order nonlinear optical properties. To incorporate such properties, organic “chromophore” molecules containing conjugated π systems situated between electron donor and acceptor groups are oriented uniformly within film that bulk structure is noncentrosymmetric. accomplished using chromophoric α,ω-bis(phosphonate) have one terminal phosphonate group “protected”...
The human protein siderocalin (Scn) inhibits bacterial iron acquisition by binding catechol siderophores. Several pathogenic bacteria respond making stealth siderophores that are not recognized Scn. Fluvibactin and vibriobactin, respectively of Vibrio fluvialis cholerae, include an oxazoline adjacent to a catechol. This chelating unit binds either in catecholate or phenolate-oxazoline coordination mode. latter has been suggested make vibriobactin siderophore without directly identifying the...
Entamoeba histolytica is the etiological agent of amebiasis, a diarrheal disease which causes amoebic liver abscesses and colitis. Approximately 50 million people are infected worldwide with E. . With only 10% developing symptomatic there still an estimated 100 000 deaths each year. Because emergence resistant strains parasite, it necessary to find treatment would be proper response this challenge. ADP-ribosylation factor (ARF) member ARF family GTP-binding proteins. These proteins...
Crystallization of a maltose-binding protein MCL1 fusion has yielded robust crystallography platform that generated the first apo crystal structure, as well five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In ligand-independent form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1...
Siderocalin/Lipocalin 2/Neutrophil Gelatinase Associated Lipocalin/24p3 is an innate immune system protein with bacteriostatic activity, acting by tightly binding and sequestering diverse catecholate mixed-type ferric siderophores from enteric bacteria mycobacteria. Bacterial virulence achieved through siderophore modifications, or utilization of alternate siderophores, can be explained evasion Siderocalin binding. has also been implicated in a wide variety disease processes, though often...
Abstract The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area significant interest when designing therapeutic agents. Previous studies show degraded in the presence IKZF1 degraders pomalidomide, and to lesser extent by CC-220. To expand our understanding basis for interaction with cereblon, we performed biophysical structural demonstrating zinc finger domains one two (ZF1-2) interact cereblon (CRBN)...
A direct binding screen of 100 000 sp3-rich molecules identified a single diastereomer macrolactam core that binds specifically to myeloid cell leukemia 1 (MCL1). comprehensive toolbox biophysical methods was applied validate the original hit and subsequent analogues also established mode competitive with NOXA BH3 peptide. X-ray crystallography ligand bound MCL1 reveals remarkable ligand/protein shape complementarity diverges from previously disclosed inhibitor costructures.
Bacterial ATP-binding cassette (ABC) importers are primary active transporters that critical for nutrient uptake. Based on structural and functional studies, ABC can be divided into two distinct classes, type I II. Type follow a strict alternating access mechanism is driven by the presence of substrate. II accept substrates in nucleotide-free state, with hydrolysis driving an inward facing conformation. The ribose transporter Escherichia coli tripartite complex consisting cytoplasmic...
Cystathionine γ-synthase (CGS) is a transulfurication enzyme that catalyzes the first specific step in l-methionine biosynthesis by reaction of O4-succinyl-l-homoserine and l-cysteine to produce l-cystathionine succinate. Controlling biosythesis, CGS an excellent potential drug target. Mycobacterium ulcerans slow-growing mycobacterium third most common form mycobacterial infection, mainly infecting people Africa, Australia Southeast Asia. Infected patients display variety skin ailments...