P1-400: TAU AND ALPHA-SYNUCLEIN SELECTIVE BINDING COMPOUNDS DERIVED FROM APRINOIA THERAPEUTIC'S PM-PBB3 BINDING-SITE FOCUSED COMPOUND COLLECTION

Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.

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Conformationally Selective Binding of Nucleotide Analogues toEscherichia coliRecA: A Ligand-Based Analysis of the RecA ATP Binding Site†

Biochemistry ◽

10.1021/bi052298h ◽

2006 ◽

Vol 45 (14) ◽

pp. 4502-4513 ◽

Cited By ~ 18

Author(s):

Tim J. Wigle ◽

Andrew M. Lee ◽

Scott F. Singleton

Keyword(s):

Binding Site ◽

Atp Binding ◽

Selective Binding ◽

Nucleotide Analogues ◽

Atp Binding Site

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P-glycoprotein possesses A 1,4-dihydropyridine-selective drug acceptor site which is alloserically coupled to a vinca-alkaloid-selective binding site

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(92)92404-l ◽

1992 ◽

Vol 188 (1) ◽

pp. 440-445 ◽

Cited By ~ 87

Author(s):

David R. Ferry ◽

Michael A. Russell ◽

Michael H. Cullen

Keyword(s):

Binding Site ◽

Vinca Alkaloid ◽

Acceptor Site ◽

Selective Binding ◽

P Glycoprotein

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DNA binding by the bacteriophage SPO1-encoded type II DNA-binding protein, transcription factor 1. Formation of nested complexes at a selective binding site.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)67166-2 ◽

1986 ◽

Vol 261 (27) ◽

pp. 12820-12827 ◽

Cited By ~ 1

Author(s):

J R Greene ◽

L M Morrissey ◽

L M Foster ◽

E P Geiduschek

Keyword(s):

Transcription Factor ◽

Dna Binding ◽

Binding Site ◽

Binding Protein ◽

Dna Binding Protein ◽

Type Ii ◽

Selective Binding ◽

Transcription Factor 1 ◽

Protein Transcription

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Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: Implications for Parkinson’s disease

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2012.05.024 ◽

2012 ◽

Vol 53 (4) ◽

pp. 993-1003 ◽

Cited By ~ 99

Author(s):

Almas Siddiqui ◽

Shankar J. Chinta ◽

Jyothi K. Mallajosyula ◽

Subramanian Rajagopolan ◽

Ingrid Hanson ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Function ◽

Alpha Synuclein ◽

Selective Binding

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Columnar aggregates of crown ether substituted phthalocyanines perpendicularly anchored on a surface via a selective binding site

Journal of Porphyrins and Phthalocyanines ◽

10.1142/s1088424602000701 ◽

2002 ◽

Vol 06 (09) ◽

pp. 563-570 ◽

Cited By ~ 9

Author(s):

Thierry Thami ◽

Christophe Chassenieux ◽

Christian Fretigny ◽

Jean-Paul Roger ◽

Felix Steybe

Keyword(s):

Crown Ether ◽

Binding Site ◽

Binding Sites ◽

Silica Surface ◽

Specific Binding ◽

Selective Binding ◽

Force Microscopy ◽

Specific Binding Sites ◽

Atomic Force ◽

Uv Visible

The purpose of this work is to anchor perpendicularly to a surface the aggregates obtained by complexation of crown-ether substituted lutetium bisphthalocyanine, [(15 C 5)4 Pc ]2 Lu , in the presence of KSCN . In order to orientate these aggregates perpendicularly to the substrate, silica surface is grafted with an unsymmetrical lutetium bisphthalocyanine substituted, on one macrocycle by four crown ether subunits, and on the other one with four lateral chains terminated by a carboxylic group. The latter compound is used as a selective binding site to anchor pillar-like aggregates formed in solution. The aggregates were characterized in a mixture of chloroformic based solution by UV-visible and light scattering experiments and gave evidence for the formation of rod-like particles in the presence of excess of KSCN . Then, the aggregates were deposited on surfaces and their morphologies were studied by atomic force microscopy (AFM). In the case of substrates having non-specific binding sites such as silica and functionalized silica with 3-trimethoxy-propylaminosilane, rods were observed lying parallel on the surface. In the case of the substrate grafted with the selective binding site, single columns of these supramolecular assemblies perpendicular to the surface have been observed by AFM.

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