Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design

Liang, Jie; Edelsbrunner, Herbert; Woodward, Clare

doi:10.1002/pro.5560070905

Cited by 964 publications

(834 citation statements)

References 59 publications

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“…6(B), cyan] by the program for identification and size characterization of surface pockets and occluded cavities, CASTp. 21,22 The volume of the cavity was indeed expanded from 209.1 Å 3 in WT I27 to 382.3 Å 3 in Y9P I27. This expansion of the cavity was brought about by significant rearrangement of the channel-forming residues.…”

Section: Resultsmentioning

confidence: 95%

Structural basis for unfolding pathway‐dependent stability of proteins: Vectorial unfolding versus global unfolding

et al. 2010

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Point mutations in proteins can have different effects on protein stability depending on the mechanism of unfolding. In the most interesting case of I27, the Ig-like module of the muscle protein titin, one point mutation (Y9P) yields opposite effects on protein stability during denaturantinduced ''global unfolding'' versus ''vectorial unfolding'' by mechanical pulling force or cellular unfolding systems. Here, we assessed the reason for the different effects of the Y9P mutation of I27 on the overall molecular stability and N-terminal unraveling by NMR. We found that the Y9P mutation causes a conformational change that is transmitted through b-sheet structures to reach the central hydrophobic core in the interior and alters its accessibility to bulk solvent, which leads to destabilization of the hydrophobic core. On the other hand, the Y9P mutation causes a bend in the backbone structure, which leads to the formation of a more stable N-terminal structure probably through enhanced hydrophobic interactions.

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Section: Resultsmentioning

confidence: 95%

Structural basis for unfolding pathway‐dependent stability of proteins: Vectorial unfolding versus global unfolding

et al. 2010

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“…The average dimensions are 12 Å in length, 8 Å in height and 5.5 to 6.5 Å in width. The program POCKET [14] was employed to determine the volume of the PhnI substrate binding pocket. The resulting volume corresponds to the unoccupied space determined by a 1.4 Å radius probe following the protein surface.…”

Section: The Catalytic Pocketmentioning

confidence: 99%

The catalytic pocket of the ring-hydroxylating dioxygenase from Sphingomonas CHY-1

Jakoncic

Jouanneau

Meyer

et al. 2007

Biochemical and Biophysical Research Communications

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Ring-hydroxylating dioxygenases are multicomponent bacterial enzymes that catalyze the first step in the oxidative degradation of aromatic hydrocarbons. The dioxygenase from Sphingomonas CHY-1 is unique in that it can oxidize a wide range of polycyclic aromatic hydrocarbons (PAHs). With a crystal structure similar to that of the seven other known dioxygenases, its catalytic domain features the largest hydrophobic substrate binding cavity characterized so far. Molecular modeling studies indicated that the catalytic cavity is large enough to accommodate a five-ring benzo [a]pyrene molecule. The predicted positions of this and other PAHs in the substrate binding pocket are consistent with the product regio-and stereo-selectivity of the enzyme. Keywordsdioxygenase; catalytic domain; mononuclear iron; bioremediation; high molecular weight polycyclic aromatic hydrocarbons The first step in the biodegradation of aromatic hydrocarbons by aerobic bacteria often involves a dihydroxylation on two adjacent carbon atoms of the aromatic ring, catalyzed by a ringhydroxylating dioxygenase (RHD). RHDs form a large family of enzymes, very diverse in terms of substrate specificity and protein sequence [1]. Their role is crucial in the degradation of many organic pollutants, including polycyclic aromatic hydrocarbons (PAHs), which are notorious for their resistance to biodegradation. Several bacteria were found to degrade PAHs but only a few have been reported to attack four and five ring PAHs [2,3]. In Sphingomonas strain CHY-1 a single RHD has been shown to be responsible for the oxidation of a wide range of PAHs [4]. This dioxygenase consists of three components, a NADH-dependent reductase (PhnA4), a ferredoxin containing a Rieske type [2Fe-2S] cluster (PhnA3), and a terminal oxygenase, PhnI, containing both a mononuclear iron [Fe 2+ ] and a [2Fe-2S] Rieske cluster [5]. Recent biochemical studies showed that the dioxygenase from strain CHY-1 was able to oxidize at least eight PAHs made of 2 to 5 aromatic rings, in contrast to most other dioxygenases, whose selectivity is limited to 2 and 3 ring PAHs [6,7,8]. A positive electron density observed in the PhnI refined three-dimensional structure served as probe in modeling different substrates in the catalytic pocket. This study presents evidence that the broad substrateCorresponding author: Vivian Stojanoff, Brookhaven National Laboratory, Upton NY 11973 US, Tel.: 1 631 344 8375; Fax: 1 631 344 3238, Email : vivian.stojanoff@gmail.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript Biochem Biophy...

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“…The Q-site Finder server identifies the energetically favourable binding sites in the protein structure [50]. The SiteMap module of the Schrödinger suite identifies the potential druggable binding sites in the protein structure and determines the binding site points on the protein surface that are merged into larger sites [51].…”

Section: Active Site Predictionmentioning

confidence: 99%

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

et al. 2016

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Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein 'Ubiquitin-conjugating enzyme E2D4' (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols. The active site region of the UBE2D4 was identified using computational tools like CASTp, Q-site Finder and SiteMap. The hydrophobic pocket which is responsible for binding with its natural receptor ubiquitin ligase CHIP (C-terminal of Hsp 70 interacting protein) was identified through proteinprotein docking study. Corroborating the results obtained from active site prediction tools and protein-protein docking study, the domain of UBE2D4 which is responsible for cancer cell progression is sorted out for further docking study. Virtual screening with large structural database like CB_Div Set and Asinex BioDesign small molecular structural database was carried out. The obtained new ligand molecules that have shown affinity towards UBE2D4 were considered for ADME prediction studies. The identified new ligand molecules with acceptable parameters of docking, ADME are considered as potent UBE2D4 enzyme inhibitors for cancer therapy.

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Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design

Cited by 964 publications

References 59 publications

Structural basis for unfolding pathway‐dependent stability of proteins: Vectorial unfolding versus global unfolding

Structural basis for unfolding pathway‐dependent stability of proteins: Vectorial unfolding versus global unfolding

The catalytic pocket of the ring-hydroxylating dioxygenase from Sphingomonas CHY-1

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

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