20 hasil untuk "Lin, Fu-Yang"

Terpene Biosynthesis: Modularity Rules

Oldfield, Eric; Lin, Fu-Yang

Angew Chem Int Ed Engl · 2011 · Inggris · PubMed Central

Terpenes are the largest class of small molecule natural products on Earth, and the most abundant by mass. Here, we summarize recent developments in elucidating the structure and function of the proteins involved in their biosynthesis. There are 6 main building blocks or modules (α,β,γ,δ,ε and ζ)…

β-Subunit Binding Is Sufficient for Ligands to Open the Integrin α(IIb)β(3) Headpiece

Lin, Fu-Yang; Zhu, Jianghai; Eng, Edward T. dkk.

J Biol Chem · 2015 · Inggris · PubMed Central

The platelet integrin α(IIb)β(3) binds to a KQAGDV motif at the fibrinogen γ-chain C terminus and to RGD motifs present in loops in many extracellular matrix proteins. These ligands bind in a groove between the integrin α and β-subunits; the basic Lys or Arg side chain hydrogen bonds to the…

High integrin α(V)β(6) affinity reached by hybrid domain deletion slows ligand-binding on-rate

Dong, Xianchi; Zhao, Bo; Lin, Fu-Yang dkk.

Proc Natl Acad Sci U S A · 2018 · Inggris · PubMed Central

The role of the hybrid domain in integrin affinity regulation is unknown, as is whether the kinetics of ligand binding is modulated by integrin affinity state. Here, we compare cell surface and soluble integrin α(V)β(6) truncation mutants for ligand-binding affinity, kinetics, and thermodynamics…

Head-to-Head Prenyl Tranferases: Anti-Infective Drug Targets

Lin, Fu-Yang; Liu, Yi-Liang; Li, Kai dkk.

J Med Chem · 2012 · Inggris · PubMed Central

We report x-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9) and 3 (SQ-109). Compound 2 binds to the S2 site with its –SCN group surrounded by 4 hydrogen bond donors. With 1, we report two structures: in both…

Bi-functional integrin degraders cause stronger anti-proliferative effects than a blocking antibody by modulating distinct downstream signaling

Monroy, Meghan F.; Krumpoch, Megan; McTeague, T. Andrew dkk.

MAbs · 2025 · Inggris · PubMed Central

Integrins play a critical role in signaling events that regulate cell adhesion, migration, and proliferation, processes that, when dysregulated, contribute to cancer progression. Recently, innovative approaches that target extracellular proteins for degradation have suggested potential in cancer…

A general chemical principle for creating closure-stabilizing integrin inhibitors

Lin, Fu-Yang; Li, Jing; Xie, Yonghua dkk.

Cell · 2022 · Inggris · PubMed Central

Integrins are validated drug targets with six approved therapeutics. However, small molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., stabilization of the high-affinity…

A recombinant technique for mapping functional sites of heterotrimeric collagen helices: Collagen IV CB3 fragment as a prototype for integrin binding

Boudko, Sergei P.; Konopka, Elizabeth H.; Kim, Woojin dkk.

J Biol Chem · 2023 · Inggris · PubMed Central

Collagen superfamily of proteins is a major component of the extracellular matrix. Defects in collagens underlie the cause of nearly 40 human genetic diseases in millions of people worldwide. Pathogenesis typically involves genetic alterations of the triple helix, a hallmark structural feature that…

Dual Dehydrosqualene/Squalene Synthase Inhibitors: Leads for Innate Immune System Based Therapeutics

Lin, Fu-Yang; Zhang, Yonghui; Hensler, Mary dkk.

ChemMedChem · 2012 · Inggris · PubMed Central

Calcium- and polyphosphate-containing acidic granules of sea urchin eggs are similar to acidocalcisomes, but are not the targets for NAADP

Ramos, Isabela B.; Miranda, Kildare; Pace, Douglas A. dkk.

Biochem J · 2010 · Inggris · PubMed Central

Acidocalcisomes are acidic calcium-storage compartments described from bacteria to humans and characterized by their high content in poly P (polyphosphate), a linear polymer of many tens to hundreds of P(i) residues linked by high-energy phosphoanhydride bonds. In the present paper we report that…

Lipophilic, pyridinium bisphosphonates are potent γδ T cell stimulators

Zhang, Yonghui; Cao, Rong; Yin, Fenglin dkk.

Angew Chem Int Ed Engl · 2010 · Inggris · PubMed Central

Mechanism of action and inhibition of dehydrosqualene synthase

Lin, Fu-Yang; Liu, Chia-I; Liu, Yi-Liang dkk.

Proc Natl Acad Sci U S A · 2010 · Inggris · PubMed Central

“Head-to-head” terpene synthases catalyze the first committed steps in sterol and carotenoid biosynthesis: the condensation of two isoprenoid diphosphates to form cyclopropylcarbinyl diphosphates, followed by ring opening. Here, we report the structures of Staphylococcus aureus dehydrosqualene…

A putative polyketide-synthesis protein XC5357 from Xanthomonas campestris: heterologous expression, crystallization and preliminary X-ray analysis

Chu, Chiao-Li; Chin, Ko-Hsin; Lin, Fu-Yang dkk.

Acta Crystallogr Sect F Struct Biol Cryst Commun · 2005 · Inggris · PubMed Central

Xanthomonas campestris pv. campestris (Xcc) is a Gram-negative yellow-pigmented bacterium and is the causative agent of black rot, one of the major worldwide diseases of cruciferous crops. It also synthesizes a variety of polyketide metabolites that lead to important antibiotics. XC5357 is a…

Phosphonosulfonates Are Potent, Selective Inhibitors of Dehydrosqualene Synthase and Staphyloxanthin Biosynthesis in Staphylococcus aureus

Song, Yongcheng; Lin, Fu-Yang; Yin, Fenglin dkk.

J Med Chem · 2009 · Inggris · PubMed Central

Staphylococcus aureus produces a golden carotenoid virulence factor called staphyloxanthin (STX), and we report here the inhibition of the enzyme, dehydrosqualene synthase (CrtM), responsible for the first committed step in STX biosynthesis. The most active compounds are halogen-substituted…

Diterpene Cyclases and the Nature of the Isoprene Fold

Cao, Rong; Zhang, Yonghui; Mann, Francis M. dkk.

Proteins · 2010 · Inggris · PubMed Central

The structures and mechanism of action of many terpene cyclases are known, but there are no structures of diterpene cyclases. Here, we propose structural models based on bioinformatics, site-directed mutagenesis, domain swapping, enzyme inhibition and spectroscopy that help explain the nature of…

Inhibition of Staphyloxanthin Virulence Factor Biosynthesis in Staphylococcus aureus: In Vitro, in Vivo, and Crystallographic Results

Song, Yongcheng; Liu, Chia-I; Lin, Fu-Yang dkk.

J Med Chem · 2009 · Inggris · PubMed Central

The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis…

HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis

Zhang, Yonghui; Lin, Fu-Yang; Li, Kai dkk.

ACS Med Chem Lett · 2012 · Inggris · PubMed Central

[Image: see text] We report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site…

E339…R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors

Shen, Yu-Fang; Chen, Yu-Hou; Chu, Shao-Ying dkk.

Proc Natl Acad Sci U S A · 2011 · Inggris · PubMed Central

The nucleoprotein (NP) of the influenza virus exists as trimers, and its tail-loop binding pocket has been suggested as a potential target for antiinfluenza therapeutics. The possibility of NP as a drug target was validated by the recent reports that nucleozin and its analogs can inhibit viral…

Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation

Zhang, Yonghui; Cao, Rong; Yin, Fenglin dkk.

J Am Chem Soc · 2009 · Inggris · PubMed Central

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anti-cancer therapeutic agents involving inhibition of farnesyl diphosphate…

Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies

Lemay, Sarah-Eve; Montesinos, Monica S.; Grobs, Yann dkk.

bioRxiv · 2024 · Inggris · PubMed Central

Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH…

Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies

Lemay, Sarah-Eve; Montesinos, Mónica S.; Grobs, Yann dkk.

Circulation · 2025 · Inggris · PubMed Central

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PAs) and progressive increase in pulmonary vascular resistance leading to right ventricular failure. Although several drugs are approved for the treatment of PAH…