scholarly journals Capturing the Reaction Pathway in Near-Atomic-Resolution Crystal Structures of HIV-1 Protease

Biochemistry ◽  
2012 ◽  
Vol 51 (39) ◽  
pp. 7726-7732 ◽  
Author(s):  
Chen-Hsiang Shen ◽  
Yunfeng Tie ◽  
Xiaxia Yu ◽  
Yuan-Fang Wang ◽  
Andrey Y. Kovalevsky ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Reaction Pathway ◽  
Atomic Resolution ◽  
Hiv 1

Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir

2007 ◽  
Vol 67 (1) ◽  
pp. 232-242 ◽  
Author(s):  
Yunfeng Tie ◽  
Andrey Y. Kovalevsky ◽  
Peter Boross ◽  
Yuan-Fang Wang ◽  
Arun K. Ghosh ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Atomic Resolution ◽  
Hiv 1

scholarly journals Activities, Crystal Structures, and Molecular Dynamics of Dihydro-1H-isoindole Derivatives, Inhibitors of HIV-1 Integrase

2012 ◽  
Vol 8 (1) ◽  
pp. 209-217 ◽  
Author(s):  
Mathieu Métifiot ◽  
Kasthuraiah Maddali ◽  
Barry C. Johnson ◽  
Stephen Hare ◽  
Steven J. Smith ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Crystal Structures ◽  
Hiv 1

Crystal Structures of HIV-1 Reverse Transcriptase in Complex with Carboxanilide Derivatives†,‡

Biochemistry ◽  
1998 ◽  
Vol 37 (41) ◽  
pp. 14394-14403 ◽  
Author(s):  
Jingshan Ren ◽  
Robert M. Esnouf ◽  
Andrew L. Hopkins ◽  
Jonathan Warren ◽  
Jan Balzarini ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Crystal Structures ◽  
Hiv 1

scholarly journals Development of a 3Mut-Apex-Stabilized Envelope Trimer That Expands HIV-1 Neutralization Breadth When Used To Boost Fusion Peptide-Directed Vaccine-Elicited Responses

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Gwo-Yu Chuang ◽  
Yen-Ting Lai ◽  
Jeffrey C. Boyington ◽  
Cheng Cheng ◽  
Hui Geng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Crystal Structures ◽  
Guinea Pigs ◽  
Fusion Peptide ◽  
Dihedral Angles ◽  
Vaccine Regimen ◽  
Closed Conformation ◽  
Clade C ◽  
Humoral Responses ◽  
Hiv 1

ABSTRACT HIV-1 envelope (Env) trimers, stabilized in a prefusion-closed conformation, can elicit humoral responses capable of neutralizing HIV-1 strains closely matched in sequence to the immunizing strain. One strategy to increase elicited neutralization breadth involves vaccine priming of immune responses against a target site of vulnerability, followed by vaccine boosting of these responses with prefusion-closed Env trimers. This strategy has succeeded at the fusion peptide (FP) site of vulnerability in eliciting cross-clade neutralizing responses in standard vaccine-test animals. However, the breadth and potency of the elicited responses have been less than optimal. Here, we identify three mutations (3mut), Met302, Leu320, and Pro329, that stabilize the apex of the Env trimer in a prefusion-closed conformation and show antigenically, structurally, and immunogenically that combining 3mut with other approaches (e.g., repair and stabilize and glycine-helix breaking) yields well-behaved clade C-Env trimers capable of boosting the breadth of FP-directed responses. Crystal structures of these trimers confirmed prefusion-closed apexes stabilized by hydrophobic patches contributed by Met302 and Leu320, with Pro329 assuming canonically restricted dihedral angles. We substituted the N-terminal eight residues of FP (FP8, residues 512 to 519) of these trimers with the second most prevalent FP8 sequence (FP8v2, AVGLGAVF) and observed a 3mut-stabilized consensus clade C-Env trimer with FP8v2 to boost the breadth elicited in guinea pigs of FP-directed responses induced by immunogens containing the most prevalent FP8 sequence (FP8v1, AVGIGAVF). Overall, 3mut can stabilize the Env trimer apex, and the resultant apex-stabilized Env trimers can be used to expand the neutralization breadth elicited against the FP site of vulnerability. IMPORTANCE A major hurdle to the development of an effective HIV-1 vaccine is the elicitation of serum responses capable of neutralizing circulating strains of HIV, which are extraordinarily diverse in sequence and often highly neutralization resistant. Recently, we showed how sera with 20 to 30% neutralization breadth could, nevertheless, be elicited in standard vaccine test animals by priming with the most prevalent N-terminal 8 residues of the HIV-1 fusion peptide (FP8), followed by boosting with a stabilized BG505-envelope (Env) trimer. Here, we show that subsequent boosting with a 3mut-apex-stabilized consensus C-Env trimer, modified to have the second most prevalent FP8 sequence, elicits higher neutralization breadth than that induced by continued boosting with the stabilized BG505-Env trimer. With increased neutralizing breadth elicited by boosting with a heterologous trimer containing the second most prevalent FP8 sequence, the fusion peptide-directed immune-focusing approach moves a step closer toward realizing an effective HIV-1 vaccine regimen.

Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase

2019 ◽  
Vol 75 (6) ◽  
pp. 592-604 ◽  
Author(s):  
Marie Haufroid ◽  
Manon Mirgaux ◽  
Laurence Leherte ◽  
Johan Wouters
Keyword(s):  
Molecular Dynamics ◽  
Reaction Mechanism ◽  
Crystal Structures ◽  
Reaction Pathway ◽  
Living Cells ◽  
Homocysteic Acid ◽  
Phosphoserine Phosphatase ◽  
Key Enzyme ◽  
The Subject ◽  
Dynamics Simulations

The equilibrium between phosphorylation and dephosphorylation is one of the most important processes that takes place in living cells. Human phosphoserine phosphatase (hPSP) is a key enzyme in the production of serine by the dephosphorylation of phospho-L-serine. It is directly involved in the biosynthesis of other important metabolites such as glycine and D-serine (a neuromodulator). hPSP is involved in the survival mechanism of cancer cells and has recently been found to be an essential biomarker. Here, three new high-resolution crystal structures of hPSP (1.5–2.0 Å) in complexes with phosphoserine and with serine, which are the substrate and the product of the reaction, respectively, and in complex with a noncleavable substrate analogue (homocysteic acid) are presented. New types of interactions take place between the enzyme and its ligands. Moreover, the loop involved in the open/closed state of the enzyme is fully refined in a totally unfolded conformation. This loop is further studied through molecular-dynamics simulations. Finally, all of these analyses allow a more complete reaction mechanism for this enzyme to be proposed which is consistent with previous publications on the subject.

Rationalizing the Geometries of the Water Oxidising Complex in the Atomic Resolution, Nominal S 3 State Crystal Structures of Photosystem II

ChemPhysChem ◽  
2020 ◽  
Vol 21 (8) ◽  
pp. 785-801 ◽  
Author(s):  
Simon Petrie ◽  
Richard Terrett ◽  
Robert Stranger ◽  
Ron J. Pace
Keyword(s):  
Photosystem Ii ◽  
Crystal Structures ◽  
Atomic Resolution
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