New Biological Insights from Better Structure Models

Touw, Wouter G.; Joosten, Robbie P.; Vriend, Gert

doi:10.1016/j.jmb.2016.02.002

Cited by 31 publications

(42 citation statements)

References 143 publications

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“…Recently, post-deposition optimization is reported to generally improve the protein structures [38] and therefore to improve the qualities of the selected DPP-4 complex structures for the FMO calculations, we re-refined and re-built all these complex structures by using PDB_REDO server, REFMAC v5.8, and Coot. Three out of four re-refined structures have improved R free values (complex structure with linagliptin 0.276 → 0.264, alogliptin 0.242 → 0.260, teneligliptin 0.279 → 0.274, sitagliptin 0.228 → 0.213), which is used for cross-validation [39], despite deleting the coordinates of the sugar chains to simplify the subsequent FMO calculations.…”

Section: Resultsmentioning

confidence: 99%

Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs – An Ab Initio Fragment Molecular Orbital Study

et al. 2016

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Dipeptidyl peptidase IV (DPP-4) enzyme is responsible for the degradation of incretins that stimulates insulin secretion and hence inhibition of DPP-4 becomes an established approach for the treatment of type 2 diabetics. We studied the interaction between DPP-4 and its inhibitor drugs (sitagliptin 1, linagliptin 2, alogliptin 3, and teneligliptin 4) quantitatively by using fragment molecular orbital calculations at the RI-MP2/cc-pVDZ level to analyze the inhibitory activities of the drugs. Apart from having common interactions with key residues, inhibitors encompassing the DPP-4 active site extensively interact widely with the hydrophobic pocket by their hydrophobic inhibitor moieties. The cumulative hydrophobic interaction becomes stronger for these inhibitors and hence linagliptin and teneligliptin have larger interaction energies, and consequently higher inhibitory activities, than their alogliptin and sitagliptin counterparts. Though effective interaction for both 2 and 3 is at subsite, 2 has a stronger binding to this subsite interacting with Trp629 and Tyr547 than 3 does. The presence of triazolopiperazine and piperazine moiety in 1 and 4, respectively, provides the interaction to the S2 extensive subsite; however, the latter’s superior inhibitory activity is not only due to a relatively tighter binding to the S2 extensive subsite, but also due to the interactions to the S1 subsite. The calculated hydrophobic interfragment interaction energies correlate well with the experimental binding affinities (KD) and inhibitory activities (IC50) of the DPP-4 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs – An Ab Initio Fragment Molecular Orbital Study

et al. 2016

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“…[63] Fletcher et al [65] und van Gunsteren et al, GROMOS. [64] Fletcher et al [65] [79][80][81] und, falls nçtig, deren Verbesserung. [81] Diesbezüglich ist es interessant, das Schicksal der oben diskutierten, stark verzerrten Strukturen aus Tabelle 3 zu verfolgen.…”

Section: Genauigkeit Der Funktion Qðrþ Zur Verknüpfung Der Beobachtbaunclassified

“…[79,80] In Anbetracht der Anzahl von Schritten, die im Laufe des Strukturverfeinerungsprozesses schiefgehen kçnnen, [81,135,136] ist es sehr wahrscheinlich, dass eine große Zahl von teilweise fehlerhaften bzw. nicht optimalen Strukturen existiert.…”

Section: Kontaminierung Von Strukturdatenbanken Durch Fehlerhafte Strunclassified

“…nicht optimalen Strukturen existiert. [81] Dies unterstreicht wie wichtig es ist, in der Lage zu sein, die in der PDB abgelegten Strukturen zu korrigieren, wenn robustere Verfahren zur Strukturbestimmung aus Messdaten beobachtbarer Grçßen [134] zur Verfügung stehen, bzw. die bestimmten Strukturen in Hinblick auf geometrische und energetische Kriterien zu überprüfen.…”

Section: Kontaminierung Von Strukturdatenbanken Durch Fehlerhafte Strunclassified

“…die bestimmten Strukturen in Hinblick auf geometrische und energetische Kriterien zu überprüfen. [81] Dies ist insbesondere dann von Bedeutung, wenn die auf diese Weise neu erhaltenen Strukturen eine bessere Übereinstimmung mit den Messdaten [137] aufweisen, als die bereits existierenden Strukturen. Es betont außerdem die Notwendigkeit, dass alle Strukturen zusammen mit den Werten der Observablen, wie NOE-Abstandsschranken, 3 J-Kopplungskonstanten und Strukturfaktoramplituden hinterlegt werden, sowie mit den Kraftfeldern und Simulationsprotokollen, die zu deren Erzeugung verwendet wurden.…”

Section: Kontaminierung Von Strukturdatenbanken Durch Fehlerhafte Strunclassified

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Bestimmung von Strukturinformation aus experimentellen Messdaten für Biomoleküle

et al. 2016

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Deriving Structural Information from Experimentally Measured Data on Biomolecules

et al. 2016

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During the past half century, the number and accuracy of experimental techniques that can deliver values of observables for biomolecular systems have been steadily increasing. The conversion of a measured value Q of an observable quantity Q into structural information is, however, a task beset with theoretical and practical problems: 1) insufficient or inaccurate values of Q , 2) inaccuracies in the function Q(r→) used to relate the quantity Q to structure r→ , 3) how to account for the averaging inherent in the measurement of Q , 4) how to handle the possible multiple-valuedness of the inverse r→(Q) of the function Q(r→) , to mention a few. These apply to a variety of observable quantities Q and measurement techniques such as X-ray and neutron diffraction, small-angle and wide-angle X-ray scattering, free-electron laser imaging, cryo-electron microscopy, nuclear magnetic resonance, electron paramagnetic resonance, infrared and Raman spectroscopy, circular dichroism, Förster resonance energy transfer, atomic force microscopy and ion-mobility mass spectrometry. The process of deriving structural information from measured data is reviewed with an eye to non-experts and newcomers in the field using examples from the literature of the effect of the various choices and approximations involved in the process. A list of choices to be avoided is provided.

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New Biological Insights from Better Structure Models

Cited by 31 publications

References 143 publications

Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs – An Ab Initio Fragment Molecular Orbital Study

Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs – An Ab Initio Fragment Molecular Orbital Study

Bestimmung von Strukturinformation aus experimentellen Messdaten für Biomoleküle

Deriving Structural Information from Experimentally Measured Data on Biomolecules

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