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Terrence R. Burke Jr., Ph.D.

Terrence R. Burke Jr., Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
  • Building 376, Room 210
  • Frederick, MD 21702-1201
  • 301-846-5906
  • burkete@nih.gov
Chemical Biology Laboratory

RESEARCH SUMMARY

Dr. Burke utilizes bioorganic and medicinal chemistry to prepare new biologically-active molecules, with an emphasis on peptides and peptide mimetics. His recent work has dealt with the development of inhibitors directed against phosphor-dependent protein-protein interactions, HIV-1 integrase and protein-tyrosine phosphatases. He is also engaged in developing antibody-drug conjugates. Link to additional information about Dr. Burke's research.

Areas of Expertise

1) bioorganic and medicinal chemistry 2) peptide and peptide mimetic chemistry 3) inhibitors of phospho-dependent protein-protein interactions (PPIs) 4) HIV integrase inhibitors 5) antibody-drug conjugates (ADCs) 6) protein-tyrosine phosphatase inhibitors

Publications

Selected Key Publications

Structural basis for strand-transfer inhibitor binding to HIV intasomes

Passos DO, Li M, Jóźwik IK, Zhao XZ, Santos-Martins D, Yang R, Smith SJ, Jeon Y, Forli S, Hughes SH, Burke TR Jr, Craigie R, Lyumkis D
Science. 367(6479): 810-14, 2020. [ Journal Article ]

Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening

Lountos GT, Zhao XZ, Kiselev E, Tropea JE, Needle D, Pommier Y, Burke TR, Waugh DS
Nucleic Acids Res. 47(19): 10134-50, 2019. [ Journal Article ]

Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

Lu X, Nowicka U, Sridharan V, Liu F, Randles L, Hymel D, Dyba M, Tarasov SG, Tarasova NI, Zhao XZ, Hamazaki J, Murata S, Burke TR Jr, Walters KJ
Nat Commun.. 8: 15540, 2017. [ Journal Article ]

A route to imidazolium-containing phosphopeptide macrocycles

Qian, W.-J.; Park, J.-E.; Grant, R.; Lai, C.C.; Kelley, J.A.; Yaffe, M.B.; Lee, K.S.; Burke, T.R., Jr.
Biopolymers Peptide Science. 104: 663-673, 2015. [ Journal Article ]

HIV-1 integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant integrases

Zhao, X.Z.; Smith, S.J.; Maskell, D.P.; Metifiot, M.; Pye, V.E.; Fesen, K.; Marchand, C.; Pommier, Y.; Cherepanov, P.; Hughes, S.H.; Burke, T.R., Jr
ACS Chemical Biology. 11: 1074-1081, 2016. [ Journal Article ]

Job Vacancies

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Team

Postbaccalaureate Fellow (CRTA)
Idris Barakat, B.S.
Postdoctoral Fellow (Visiting)
Ramesh Chingle, Ph.D.
Postbaccalaureate Fellow (CRTA)
Arvin Karbasi, B.S.
Postdoctoral Fellow (Visiting)
Samanthreddy Kedika , Ph.D.
Postdoctoral Fellow (Visiting)
Pankaj Mahajan, Ph.D.
Senior Research Assistant
Steven J Smith, Ph.D.

Covers

Blue hand working puppet of man on strings with molecules behind

Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles

Published Date

Targeting protein – protein interactions (PPIs) has emerged as an important area of discovery for anticancer therapeutic development. In the case of phospho-dependent PPIs, such as the polo-like kinase 1(Plk1) polo-box domain (PBD), a phosphorylated protein residue can provide high-affinity recognition and binding to target protein hot spots. Developing antagonists of the Plk1 PBD can be particularly challenging if one relies solely on interactions within and proximal to the phospho-binding pocket. Fortunately, the affinity of phosphor dependent PPI antagonists can be significantly enhanced by taking advantage of interactions in both the phospho-binding site and hidden “cryptic” pockets that may be revealed on ligand binding. In our current paper, we describe the design and synthesis of macrocyclic peptide mimetics directed against the Plk1 PBD, which are characterized by a new glutamic acid analog that simultaneously serves as a ring-closing junction that provides accesses to a cryptic binding pocket, while at the same time achieving proper orientation of a phosphothreonine (pT) residue for optimal interaction in the signature phospho-binding pocket. Macrocycles prepared with this new amino acid analog introduce additional hydrogen-bonding interactions not found in the open-chain linear parent peptide. It is noteworthy that this new glutamic acid-based amino acid analog represents the first example of extremely high affinity ligands where access to the cryptic pocket from the pT-2 position is made possible with a residue that is not based on histidine. The concepts employed in the design and synthesis of these new macrocyclic peptide mimetics should be useful for further studies directed against the Plk1 PBD and potentially for ligands directed against other PPI targets.

This article can be accessed directly from the Royal Society of Chemistry at Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles - Organic & Biomolecular Chemistry (RSC Publishing)

Citation

Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles by David Hymel, Kohei Tsuji, Robert A. Grant, Ramesh M. Chingle, Dominique L. Kunciw, Michael B. Yaffe and Terrence R. Burke, Jr.* in Organic & Biomolecular Chemistry, 202119, 7843-7854.

Ribbon model of INSTIs bound to HIV-1 IN.

HIV‑1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants

Published Date

The inside cover shows INSTIs bound to HIV-1 IN.  Compound 5j (magenta) was docked onto the structures of 4d (yellow) and BIC (green) bound to the active site of HIV-1 IN; the surface of IN is shown in white. The surface envelope of the unprocessed 3′ end of the vDNA is shown as brown mesh. Ordered water molecules bound to the active site of IN in the absence of a bound INSTI are shown in cyan.

Abstract: Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS. INSTIs have a polycyclic core with heteroatom triads, chelate the metal ions at the active site, and have a halobenzyl group that interacts with viral DNA attached to the core by a flexible linker. The most broadly effective INSTIs inhibit both wild-type (WT) integrase (IN) and a variety of well-known mutants. However, because there are mutations that reduce the potency of all the available INSTIs, new and better compounds are needed. Models based on recent structures of HIV-1 and red-capped mangabey SIV INs suggest modifications in the INSTI structures that could enhance interactions with the 3′-terminal adenosine of the viral DNA, which could improve performance against INSTI resistant mutants. We designed and tested a series of INSTIs having modifications to their naphthyridine scaffold. One of the new compounds retained good potency against an expanded panel of HIV-1 IN mutants that we tested. Our results suggest the possibility of designing inhibitors that combine the best features of the existing compounds, which could provide additional efficacy against known HIV-1 IN mutants.

Citation

Steven J. Smith, Xue Zhi Zhao, Dario Oliveira Passos, Valerie E. Pye, Peter Cherepanov, Dmitry LyumkisTerrence R. Burke, Jr., and Stephen H. Hughes* in ACS Infectious Diseases, 20217, 1469-1482

Ribbon showing small molecules binding to TDP1

Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites

Published Date

We now report examining a 21 000-member library of drug-like Small Molecules in Microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified structurally similar N,2-diphenylimidazo[1,2-a]pyrazin-3-amines as TDP1 binders and catalytic inhibitors. We then explored the core heterocycle skeleton using one-pot Groebke–Blackburn–Bienayme multicomponent reactions and arrived at analogs having higher inhibitory potencies. Solving TDP1 co-crystal structures of a subset of compounds showed their binding at the TDP1 catalytic site, while mimicking substrate interactions. Although our original fragment screen differed significantly from the current microarray protocol, both methods identified ligand–protein interactions containing highly similar elements. Importantly inhibitors identified through the SMM approach show competitive inhibition against TDP1 and access the catalytic phosphate-binding pocket, while simultaneously providing extensions into both the substrate DNA and peptide-binding channels. As such, they represent a platform for further elaboration of trivalent ligands, that could serve as a new genre of potent TDP1 inhibitors

Citation

Xue Zhi Zhao, Evgeny Kiselev, George T. Lountos, Wenjie Wang, Joseph E. Tropea, Danielle Needle, Thomas A. Hilimire, John S. Schneekloth, Jr, David S. Waugh, Yves Pommier and Terrence R. Burke, Jr. Chemical Science, 2021, 12, 3876 - 3884

space filling model of Plk1 inhibitor BI2536

A new genre of fluorescence recovery assay to evaluate polo-like kinase 1 ATP-competitive inhibitors

Published Date

Using a probe consisting of a fluorescein-labeled variant of the potent polo-like kinase 1 (Plk1) inhibitor BI2536 [FITC-PEG-Lys(BI2536) 4], we were able to determine half maximal inhibitory concentration (IC50) of ATP-competitive Type 1 inhibitors of Plk1 by means of a fluorescence recovery assay. This methodology represents a cost-effective and simple alternative to traditional kinase assays for initial screening of potential Plk1 inhibitors.

See: A new genre of fluorescence recovery assay to evaluate polo-like kinase 1 ATP-competitive inhibitors by Kohei Tsuji, David Hymel and Terrence R. Burke, Jr. in Analytical Methods, 2020, 12, 4418 -4421.

This article can be accessed directly from the Royal Society of Chemistry at https://pubs.rsc.org/en/content/articlelanding/2020/AY/D0AY01223H#!divAbstract

Citation

 Analytical Methods, 2020, 12, 4418 -4421.

Peptide-Protein interactions using oxime ligation.

Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions

Published Date

Protein–protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended character of many PPIs can render developing inhibitors against them as exceptionally difficult. Yet this problem can be made tractable by taking advantage of the fact that large interacting surfaces are often characterized by confined “hot spot” regions, where interactions contribute disproportionately to overall binding energies. Peptides afford valuable starting points for developing PPI inhibitors because of their high degrees of functional diversity and conformational adaptability. Unfortunately, contacts afforded by the 20 natural amino acids may be suboptimal and inefficient for accessing both canonical binding interactions and transient “cryptic” binding pockets. Oxime ligation represents a class of biocompatible “click” chemistry that allows the structural diversity of libraries of aldehydes to be rapidly evaluated within the context of a parent oxime-containing peptide platform. Importantly, oxime ligation represents a form of post solid-phase diversification, which provides a facile and empirical means of identifying unanticipated protein–peptide interactions that may substantially increase binding affinities and selectivity. The current review will focus on the authors’ use of peptide ligation to optimize PPI antagonists directed against several targets, including tumor susceptibility gene 101 (Tsg101), protein tyrosine phosphatases (PTPases) and the polo-like kinase 1 (Plk1). This should provide insights that can be broadly directed against an almost unlimited range of physiologically important PPIs.

See: Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions by Xue Zhi Zhao, Fa Liu and Terrence R. Burke Jr. in Molecules, 2020, 25 (12), 2807.

Citation

Molecules, 2020, 25 (12), 2807.

Crystal structure of TDP1 bound to one of the small molecule inhibitors

Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening

Published Date

Tyrosyl DNA-phosphodiesterase I (TDP1) repairs type IB topoisomerase (TOP1) cleavage complexes generated by TOP1 inhibitors commonly used as anticancer agents. TDP1 also removes DNA 3′ end blocking lesions generated by chain-terminating nucleosides and alkylating agents, and base oxidation both in the nuclear and mitochondrial genomes. Combination therapy with TDP1 inhibitors is proposed to synergize with topoisomerase targeting drugs to enhance selectivity against cancer cells exhibiting deficiencies in parallel DNA repair pathways. A crystallographic fragment screening campaign against the catalytic domain of TDP1 was conducted to identify new lead compounds. Crystal structures revealed two fragments that bind to the TDP1 active site and exhibit inhibitory activity against TDP1. These fragments occupy a similar position in the TDP1 active site as seen in prior crystal structures of TDP1 with bound vanadate, a transition state mimic. Using structural insights into fragment binding, several fragment derivatives have been prepared and evaluated in biochemical assays. These results demonstrate that fragment-based methods can be a highly feasible approach toward the discovery of small-molecule chemical scaffolds to target TDP1, and for the first time, we provide co-crystal structures of small molecule inhibitors bound to TDP1, which could serve for the rational development of medicinal TDP1 inhibitors.

Citation

See: Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening by George T. Lountos, Xue Zhi Zhao, Evgeny Kiselev, Joseph E. Tropea, Danielle Needle, Yves Pommier, Terrence R. Burke, Jr. and David S. Waugh in Nucleic Acids Research201947, 10134–10150.

2 inhibitors depicted binding within the hydrophobic pocket on the surface of the PBD..

Development of Highly Selective 1,2,3-Triazole-containing Peptidic Polo-like Kinase 1 Polo-box Domain-binding Inhibitors

Published Date

Cover Story: Two highly selective triazole-containing peptidic polo-like kinase 1 (Plk1) polo-box domain (PBD)-binding inhibitors (3d in green and 4b in orange) are depicted, binding within the hydrophobic “cryptic” binding pocket on the surface of the Plk1 PBD (light blue). The placement was guided by our previously reported X-ray crystal structure of PBD-bound parent peptide (2a) (PDB accession code: 3RQ7), whose binding pocket is highlighted in yellow. These ligands retain the high PBD-binding affinity of the parent peptide, while showing desirable enhanced selectivity for the PBD of Plk1 relative to the PBDs of Plk2 and Plk3.

Members of the polo-like kinase (Plk) family of serine/threonine protein kinases play crucial roles in cell cycle regulation and proliferation. Of five Plks (Plk1 – 5), Plk1 is recognized as an anticancer drug target. Plk1 contains multiple structural components that are important for its proper biological function. These include an N-terminal catalytic domain and a C-terminal non-catalytic polo-box domain (PBD). The PBD binds to phosphothreonine (pT) and phosphoserine-containing sequences. Blocking PBD-dependent interactions offers a potential means of down-regulating Plk1 function that is distinct from targeting its ATP-binding site. Previously, we demonstrated by tethering alkylphenyl chains from the N(π)-position of the His residue in the 5-mer PLHSpT, that we were able to access a hydrophobic "cryptic" binding pocket on the surface of the PBD, and in so doing enhance binding affinities by approximately 1000-fold. More recently, we optimized these PBD-ligand interactions using an oxime ligation-based strategy. Herein, using azide-alkyne cycloaddition reactions, we explore new triazole-containing PBD-binding antagonists. Some of these ligands retain the high PBD-binding affinity of the parent peptide, while showing desirable enhanced selectivity for the PBD of Plk1 relative to the PBDs of Plk2 and Plk3.

Citation

Zhao, X. Z.; Tsuji, K.; Hyman, D. M.; Burke, T. R., Jr. Development of highly selective 1,2,3-triazole-containing peptidic polo-like kinase 1 polo-box domain-binding inhibitors Molecules 2019, 24, 1488 (doi:10.3390/molecules24081488).

Reduction of size with retention of PlK-1 binding affinity with enhanced Plk2, Plk3 selectivity.

Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors

Published Date

Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLH∗SpT (2a) (where H∗ indicates the presence of a –(CH2)8Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. The resulting macrocycles are highly potent in biochemical assays and maintain good target selectivity for the Plk1 PBD versus the PBDs of Plk2 and Plk3. Importantly, as exemplified by 5d, our current approach permits deletion of the N-terminal “Pro-Leu” motif to yield tripeptide ligands with decreased molecular weight, which retain high affinity and show improved target selectivity. These findings could fundamentally impact the future development of peptide macrocycles in general and Plk1 PBD-binding peptide mimetics in particular.

Citation

David Hymel, Robert A. Grant, Kohei Tsuji, Michael B. Yaffe and Terrence R. Burke in Bioorganic & Medicinal Chemistry Letter, 2018, 28 (19), 3202-3205.

A 7-mer peptide based on the shortened Vpr sequence containing a biotin group and a photo-reactive residue

HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence

Published Date

HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC). Coordinated interactions within the PIC are important for viral replication. Herein, we report a 7-mer peptide based on the shortened Vpr (69–75) sequence containing a biotin group and a photo-reactive benzoylphenylalanyl residue, and which exhibits low micromolar IN inhibitory potency. Photo-crosslinking experiments have indicated that the peptide directly binds IN. The peptide does not interfere with IN-DNA interactions or induce higher-order, aberrant IN multimerization, suggesting a mode of action for the peptide that is distinct from clinically used INSTIs and developmental allosteric IN inhibitors. This compact Vpr-derived peptide may serve as a valuable pharmacological tool to identify a potential new pharmacologic site.

Citation

 Xue Zhi Zhao, Mathieu Métifiot, Evgeny Kiselev, Jacques J. Kessi, Kasthuraiah Maddali, Christophe Marchand, Mamuka Kvaratskhelia, Yves Pommier and Terrence R. Burke Jr. in Molecules, 201823 (8), 1858.

Cover of Journal of Medicinal Chemistry September 14, 2017

Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors

Published Date

Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistancecausing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described. View the article.

Citation

Xue Zhi Zhao, Steven J. Smith, Daniel P. Maskell, Mathieu Metífiot, Valerie E. Pye, Katherine Fesen, Christophe Marchand, Yves Pommier, Peter Cherepanov, Stephen H. Hughes, and Terrence R. Burke, Jr. in J. Med. Chem. 201760, 7315-7332.

Cover of Bioorganic & Medicinal Chemistry Letters Oct. 15, 2016

Application of oxime-diversification to optimize ligand interactions within a cryptic pocket of the polo-like kinase 1 polo-box domain

Published Date

By a process involving initial screening of a set of 87 aldehydes using an oxime ligation-based strategy, we were able to achieve a several-fold affinity enhancement over one of the most potent previously known polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors. This improved binding may result by accessing a newly identified auxiliary region proximal to a key hydrophobic cryptic pocket on the surface of the protein. Our findings could have general applicability to the design of PBD-binding antagonists. 
Cover design by Joseph Myer

Citation

Xue Zhi Zhao, David Hymel and Terrence R. Burke, Jr. in Bioorganic & Medicinal Chemistry Letters2016, 26, 5009-5012. 

ACS Chemical Biology cover - Vol. 11, No. 2, Apr. 15, 2016

HIV‑1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases

Published Date

On the cover: Mutant forms of HIV-1 IN reduce the therapeutic effectiveness of integrase strand transfer inhibitors (INSTIs). The cover figure shows the IN of prototype foamy virus complexed to a novel INSTI (gold) that retains potency against resistant mutants of HIV-1 IN. Overlain are the host and viral DNA substrates (blue and green, respectively), showing substrate mimicry by the inhibitor.

Cover design by Joseph Myer

Citation

Xue Zhi Zhao, Steven J. Smith, Daniel P. Maskell, Mathieu Metifiot, Valerie E. Pye, Katherine Fesen, Christophe Marchand, Yves Pommier, Peter Cherepanov, Stephen H. Hughes and Terrence R. Burke, Jr. in ACS Chemical Biology, 20165, 11 , 1074-1081.

Cover of Peptide Science, Nov. 2015

Neighbor-Directed Histidine N (s)–Alkylation: A Route to Imidazolium-Containing Phosphopeptide Macrocycles-Biopolymers

Published Date

Our recently discovered, selective, on-resin route to N(s)-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In this, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. Interestingly, these cationic moieties subsequently serve to charge-mask the phosphoamino acid group that directed their formation. Neighbor-directed histidine N(s)-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts.

See also: Editorial Information

Citation

Wen-Jian Qian, Jung-Eun Park, Robert Grant, Christopher C. Lai, James A. Kelley, Michael B. Yaffe, Kyung S. Lee and Terrence R. Burke Jr. in Peptide Science2015104, 663–673.3.

Cover of ChemBioChem, June 18, 2012

Peptoid–Peptide Hybrid Ligands Targeting the Polo Box Domain of Polo-Like Kinase 1k

Published Date

The cover picture shows the binding of a PLHSpT derivative, 6q, to the polo-like kinase 1 (Plk1) polo-box domain (PBD), thereby uncovering a new hydrophobic channel (magnified upper right), which is absent in the unliganded protein (magnified lower left). The authors explain how, as a consequence of the additional interaction with the channel, the peptide binds to the Plk1 PBD with a binding affinity more than two orders of magnitude higher. The background image of a stained cell nucleus depicts how this binding results in interference with Plk1 (red dots)-dependent bipolar spindle formation (green), and this ultimately leads to mitotic block and apoptotic cell death in cultured cancer cells. 

Citation

Fa Liu, Jung-Eun Park, Wen-Jian Qian, Dan Lim, Andrej Scharow, Thorsten Berg, Michael B. Yaffe, Kyung S. Lee*, and Terrence R. Burke Jr., in ChemBioChem 201213, 1291-1296.

Cover of Biopolymers Peptide Science, July 5, 2011

Application of Ring-Closing Metathesis to Grb2 SH3 Domain-Binding Peptides

Published Date

In silico-generated hypothetical interactions of a ring-closing metathesis-macrocylized peptide bound to the amino terminal SH3 domain of the growth factor receptor bound protein 2 (Grb2). The complex was derived from the NMR solution structure of the bound parent peptide, Ac-V-P-P-P-V-P-P-R-R-R-amide (Protein Data Bank: 3GBQ). The protein surface is shown as electrostatic potential (blue = positive; red = negative).

Citation

Fa Liu, Alessio Giubellino, Philip C. Simister, Wenjian Qian, Michael C. Giano, Stephan M. Feller, Donald P. Bottaro and Terrence R. Burke Jr. in Peptide Science201196 (6), 780–788.

Cover of The Proceedings of the National Academy of Sciences, USA, June 27, 2006

Discovery of a small-molecule HIV-1 integrase inhibitor-binding site

Published Date

The lowest energy-binding conformation of an inhibitor bound to the dimeric interface of HIV-1 integrase core domain. The yellow region represents a unique allosteric binding site identified by affinity labeling and mass spectrometry and validated through mutagenesis. This site can provide a potential platform for the rational design of inhibitors selective for disruption of integrase multimerization.

Citation

See: Laith Q. Al-Mawsawi, Valery Fikkert, Raveendra Dayam, Myriam Witvrouw, Terrence R. Burke, Jr., Christoph H. Borchers and Nouri Neamati in PNAS 2006103 (26), 10080-10085.

Cover of Biochemical Pharmacology, August 9, 1996

Cell protein cross-linking by erbstatin and related compounds

Published Date

The scheme depicts a possible mechanism of cross-linking by erbstatin and related analogues. A mechanism of action is proposed which involves initial oxidation to reactive quinone intermediates that subsequently cross-link protein nucleophiles via multiple 1,4-Michael-type additions. Similar alkylation of protein by protein-tyrosine kinase inhibitors, such as herbimycin A, has been invoked. 

Citation

See: Caroline Stanwell, Bin Ye, Stuart H Yuspa and Terrence R Burke Jr. in Biochemical Pharmacology 199652 (3), 475-480.