Influence of ligand binding on structure and thermostability of human α(1) -acid glycoprotein

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11320%2F16%3A10314213" target="_blank" >RIV/00216208:11320/16:10314213 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1002/jmr.2496" target="_blank" >http://dx.doi.org/10.1002/jmr.2496</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/jmr.2496" target="_blank" >10.1002/jmr.2496</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Influence of ligand binding on structure and thermostability of human α(1) -acid glycoprotein

Popis výsledku v původním jazyce

Ligand binding of neutral progesterone, basic propranolol, and acidic warfarin to human α(1)-acid glycoprotein (AGP) was investigated by Raman spectroscopy. The binding itself is characterized by a uniform conformational shift in which a tryptophan residue is involved. Slight differences corresponding to different contacts of the individual ligands inside the β-barrel are described. Results are compared with in silico ligand docking into the available crystal structure of deglycosylated AGP using quantum/molecular mechanics. Calculated binding energies are -18.2, -14.5, and -11.5 kcal/mol for warfarin, propranolol, and progesterone, respectively. These calculations are consistent with Raman difference spectroscopy; nevertheless, minor discrepancies in the precise positions of the ligands point to structural differences between deglycosylated and native AGP. Thermal dynamics of AGP with/without bounded warfarin was followed by Raman spectroscopy in a temperature range of 10-95 oC and analyzed by principal component analysis. With increasing temperature, a slight decrease of α-helical content is observed that coincides with an increase in β-sheet content. Above 45 oC, also β-strands tend to unfold, and the observed decrease in β-sheet coincides with an increase of β-turns accompanied by a conformational shift of the nearby disulfide bridge from high-energy trans-gauche-trans to more relaxed gauche-gauche-trans. This major rearrangement in the vicinity of the bridge is not only characterized by unfolding of the β-sheet but also by subsequent ligand release. Hereby, ligand binding alters the protein dynamics, and the more rigid protein-ligand complex shows an improved thermal stability, a finding that contributes to the reported chaperone-like function of AGP.

Název v anglickém jazyce

Influence of ligand binding on structure and thermostability of human α(1) -acid glycoprotein

Popis výsledku anglicky

Ligand binding of neutral progesterone, basic propranolol, and acidic warfarin to human α(1)-acid glycoprotein (AGP) was investigated by Raman spectroscopy. The binding itself is characterized by a uniform conformational shift in which a tryptophan residue is involved. Slight differences corresponding to different contacts of the individual ligands inside the β-barrel are described. Results are compared with in silico ligand docking into the available crystal structure of deglycosylated AGP using quantum/molecular mechanics. Calculated binding energies are -18.2, -14.5, and -11.5 kcal/mol for warfarin, propranolol, and progesterone, respectively. These calculations are consistent with Raman difference spectroscopy; nevertheless, minor discrepancies in the precise positions of the ligands point to structural differences between deglycosylated and native AGP. Thermal dynamics of AGP with/without bounded warfarin was followed by Raman spectroscopy in a temperature range of 10-95 oC and analyzed by principal component analysis. With increasing temperature, a slight decrease of α-helical content is observed that coincides with an increase in β-sheet content. Above 45 oC, also β-strands tend to unfold, and the observed decrease in β-sheet coincides with an increase of β-turns accompanied by a conformational shift of the nearby disulfide bridge from high-energy trans-gauche-trans to more relaxed gauche-gauche-trans. This major rearrangement in the vicinity of the bridge is not only characterized by unfolding of the β-sheet but also by subsequent ligand release. Hereby, ligand binding alters the protein dynamics, and the more rigid protein-ligand complex shows an improved thermal stability, a finding that contributes to the reported chaperone-like function of AGP.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

BO - Biofyzika

OECD FORD obor

—

Projekt

<a href="/cs/project/GP202%2F06%2FP208" target="_blank" >GP202/06/P208: Strukturní a vazebné vlastnosti lidského alfa(1)-kyselého glykoproteinu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Molecular Recognition

ISSN

0952-3499

e-ISSN

—

Svazek periodika

29

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

70-79

Kód UT WoS článku

000368640400002

EID výsledku v databázi Scopus

2-s2.0-84955666818