scholarly journals Structural Basis for Differential Binding of the Interleukin-8 Monomer and Dimer to the CXCR1 N-Domain: Role of Coupled Interactions and Dynamics

Biochemistry ◽  
2009 ◽  
Vol 48 (37) ◽  
pp. 8795-8805 ◽  
Author(s):  
Aishwarya Ravindran ◽  
Prem Raj B. Joseph ◽  
Krishna Rajarathnam
Keyword(s):  
Interleukin 8 ◽  
Structural Basis ◽  
Differential Binding

scholarly journals Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

2019 ◽  
Author(s):  
Johannes F. Van Agthoven ◽  
Hengameh Shams ◽  
Frank V. Cochran ◽  
José L. Alonso ◽  
James R. Kintzing ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Critical Role ◽  
Md Simulations ◽  
Structural Basis ◽  
Conformational Selection ◽  
Drug Candidates ◽  
Tumor Survival ◽  
Differential Binding ◽  
Integrin Ligand

AbstractIntegrins αVβ3 and α5β1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)-containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both αVβ3 and α5β1, whereas 2.5D is αVβ3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with αVβ3. These data, combined with MD simulations and mutational studies, revealed a critical role of two αVβ3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an αVβ3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.

scholarly journals Structural basis of GTPase-mediated mitochondrial ribosome biogenesis and recycling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hauke S. Hillen ◽  
Elena Lavdovskaia ◽  
Franziska Nadler ◽  
Elisa Hanitsch ◽  
Andreas Linden ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Peptidyl Transferase ◽  
Mitochondrial Ribosomes ◽  
Mitochondrial Ribosome ◽  
In Vitro Reconstitution

AbstractRibosome biogenesis requires auxiliary factors to promote folding and assembly of ribosomal proteins and RNA. Particularly, maturation of the peptidyl transferase center (PTC) is mediated by conserved GTPases, but the molecular basis is poorly understood. Here, we define the mechanism of GTPase-driven maturation of the human mitochondrial large ribosomal subunit (mtLSU) using endogenous complex purification, in vitro reconstitution and cryo-EM. Structures of transient native mtLSU assembly intermediates that accumulate in GTPBP6-deficient cells reveal how the biogenesis factors GTPBP5, MTERF4 and NSUN4 facilitate PTC folding. Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state. Additionally, cryo-EM analysis of GTPBP6-treated mature mitochondrial ribosomes reveals the structural basis for the dual-role of GTPBP6 in ribosome biogenesis and recycling. Together, these results provide a framework for understanding step-wise PTC folding as a critical conserved quality control checkpoint.

scholarly journals Structural basis for a complex I mutation that blocks pathological ROS production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhan Yin ◽  
Nils Burger ◽  
Duvaraka Kula-Alwar ◽  
Dunja Aksentijević ◽  
Hannah R. Bridges ◽  
...  
Keyword(s):  
Point Mutation ◽  
Complex I ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Ros Production

AbstractMitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

Structural basis of ventricular remodeling: Role of the myocyte

2004 ◽  
Vol 1 (1) ◽  
pp. 5-8 ◽  
Author(s):  
Faqian Li ◽  
Xuejun Wang ◽  
Xian Ping Yi ◽  
A. Martin Gerdes
Keyword(s):  
Ventricular Remodeling ◽  
Structural Basis

scholarly journals The role of endothelial interleukin-8/NADPH oxidase 1 axis in sepsis

Immunology ◽  
2010 ◽  
Vol 131 (3) ◽  
pp. 331-339 ◽  
Author(s):  
Takashi Miyoshi ◽  
Kouhei Yamashita ◽  
Toshiyuki Arai ◽  
Kokichi Yamamoto ◽  
Kiyomi Mizugishi ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Interleukin 8 ◽  
Nadph Oxidase 1

scholarly journals Structural Basis for the Inhibitory Role of Tomosyn in Exocytosis

2004 ◽  
Vol 279 (45) ◽  
pp. 47192-47200 ◽  
Author(s):  
Ajaybabu V. Pobbati ◽  
Adelia Razeto ◽  
Matthias Böddener ◽  
Stefan Becker ◽  
Dirk Fasshauer
Keyword(s):  
Structural Basis ◽  
Inhibitory Role
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