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Technology

Our Focus Our Platform Partnering Publications

Current Focus: GPCRs

GPCRs are key to human health.

G-protein coupled receptors (GPCRs) form the largest human membrane protein family with 826 identified members. Their function spans nearly all physiological functions, including metabolism, immune system regulation, heart rate, behavior and sensory system, meaning they are important therapeutic targets. To date, there are approximately 475 drugs on the market acting at over 100 unique GPCRs. Yet, more than 220 GPCRs have not yet been explored as clinical targets, representing broad untapped therapeutic potential.

GPCRs are inherently challenging targets

GPCRs are mechanistically complex. Their primary function is to recognize extracellular substances (primarily ligands) and transmit signals across the cell membrane to the inside of the cell. Extracellular ligands bind to GPCRs to induce conformational changes, which impact downstream signaling. Ligand binding can result in various activation patterns of downstream pathways including G-proteins, β-arrestins and other non-G-protein transducers, leading to both physiologic and pathologic effects.

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GPCR structural visualization is complex, making GPCR structure-based drug discovery challenging.

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Low and unstable GPCR protein expression can create significant hurdles to structural and pharmacological characterization.

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Diversity in downstream signaling pathways can lead to off-target effects by activating unintended pathways.

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Similarity among GPCR binding sites hinder efforts to design drugs with specific receptor selectivity.

The Structure solution

With an unparalleled track record in GPCR structure-based drug design, Structure’s team expertly deploys breakthrough technical advances to navigate these challenges in pursuit of innovative small molecule drugs. Our team has extensive experience with these notoriously difficult targets, including our founders who solved the first human GPCR crystal structure bound to a diffusible ligand.

Our Platform

Structure’s platform unlocks the potential of GPCRs.

Our platform integrates multiple groundbreaking technologies designed to overcome the historical limitations of GPCR drug development.

Insights into protein structure and dynamics drive intelligent drug design.

Our structure-based technology platform combines direct visualization of receptor-binding interactions with advanced simulation of molecular motion and signal transduction. This allows us to design molecules with ideal binding properties and confirmational characteristics to elicit precise downstream signaling.

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Cutting-edge computational chemistry powered by Schrodinger

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Structural techniques, including cryo-EM and X-ray crystallography

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State-of-the-art small molecule hit identification including DNA encoded library (DEL) technology and affinity mass spectrometry selections

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Medicinal chemistry along with a matrix of pharmacological assay platform

Built for speed and efficiency.

Basecamp Bio, our wholly owned subsidiary, focuses on early discovery and technology development. Basecamp Bio optimizes proprietary in-house drug discovery tools to enable the synthesis and screening of vast numbers of small molecule product candidates at a scale that is not possible to achieve with traditional methods.

We take an iterative computational approach to evaluate and optimize molecules in silico ahead of synthesis and assay. This can accelerate the lead optimization process, reduce development cost and potentially increase likelihood of clinical success compared to traditional drug discovery.

TRADITIONAL APPROACH

BASECAMP PLATFORM

Our ultimate goal:
Innovative small molecules.

Our expertise in structure-based drug design results in small molecules with enhanced activity, tailor-made signaling response and improved selectivity while maintaining ideal pharmaceutical properties. We aim to create small molecules with biologic-like activity and specificity without the inherent limitations of biologics.

Drug Discovery Partnering

Our drug discovery engine enables rapid and efficient progress to clinic-ready assets. We will explore selective partnerships to tackle challenging cell receptor targets pursued by the biopharmaceutical industry. Interested in partnering with us? Contact us today.

Why small molecules now?

With recent advances in structure-based drug discovery approaches, we can now design tailor made medicines to elicit precise downstream signaling effects to ameliorate disease. These oral small molecule drugs can now offer improved patient experience and broad access coupled with the therapeutic activity of biologics.

Presentations & Publications

Foundational Publications

Explore over two decades of publications that are the foundation of Structure’s innovative technology and approach.

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Yang Yue, Lier Liu, Li-Jie Wu, Yiran Wu, Ling Wang, Fei Li, Junlin Liu, Gye-Won Han, Bo Chen, Xi Lin, Rebecca L Brouillette, Émile Breault, Jean-Michel Longpré, Songting Shi, Hui Lei, Philippe Sarret, Raymond C Stevens, Michael A Hanson, Fei Xu “Structural insight into apelin receptor-G protein stoichiometry” Nat Struct Mol Biol. 2022 Jul;29(7):688-697. doi: 10.1038/s41594-022-00797-5. Epub 2022 Jul 11.

December 6, 2022/by eallison

C. Martin, L.E. Gimenez, S.Y. Williams, Y. Jing, Y. Wu, C. Hollanders, O. Van der Poorten, S. Gonzalez, K. Van Holsbeeck, S. Previti, A. Lamouroux, S. Zhao, D. Tourwe, R.C. Stevens, R.D. Cone, S. Ballet “Structure based design of melanocortin 4 receptor ligands based on the SHU-9119-hMC4R cocrystal structure.” J. Med. Chem. 64, 357-369 (2021). doi: 10.1021/acs.jmedchem.0c01620.

February 13, 2021/by David Anderson

J. Singla, K.L. White, R.C. Stevens, F. Abler “Assessment of scoring functions to rank the quality of 3D subtomogram clusters from cryo-electron tomography” J. Struct. Biol. Online 19 Mar (2021). doi: 10.1016/j.jsb.2021.107727.

February 13, 2021/by David Anderson

Z. Wang, T. Gurlo, A.V. Matveyenko, D. Elashoff, P. Wang, M. Rosenberger, J.A. Junge, R.C. Stevens, K.L. White, S.E. Fraser, P.C. Butler “Live-cell imaging of glucose-induced metabolic coupling of β and α cell metabolism in health and type 2 diabetes” Commun. Biol. 4, 594 (2021). doi: 10.1038/s42003-021-02113-1.

February 13, 2021/by David Anderson

F. Zhao, C. Zhang, Q. Zhou, K. Hang, X. Zou, Y. Chen, F. Wu, Q. Rao, A. Dai, W. Yin, D.D. Shen, Y. Zhang, T. Xia, R.C. Stevens, H.E. Xu, D. Yang, L. Zhao, M.W. Wang “Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.” Elife 10, e68719 (2021). doi: 10.7554/eLife.68719.

February 13, 2021/by David Anderson

J. Yu, L.E. Gimenez, C.C. Hernandez, Y. Wu, A.H. Wein, G.W. Han, K. McClary, S.R. Mittal, K. Burdsall, B. Stauch, L. Wu, S.N. Stevens, A. Peisley, S.Y. Williams, V. Chen, G.L. Millhauser, S. Zhao, R.D. Cone, R.C. Stevens “Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding” Science 368, 428-433 (2020). online 24 April 2020. doi: 10.1126/science.aaz8995. PMC7567314.

February 13, 2020/by David Anderson

M. Audet, K. Villers, J. Velasquez, M. Chu, C. Hanson, R.C. Stevens “Small-scale approach for precrystallization screening in GPCR X-ray crystallography” Nat. Protoc. 15, 144-160 (2020). doi: 10.1038/s41596-019-0259-y.

February 13, 2020/by David Anderson

R. Lamichhane, J.J. Liu, K.L. White, V. Katritch, R.C. Stevens, K. Wüthrich, D.P. Millar “Biased signaling in the G-protein-coupled receptor β2AR is governed by conformational exchange kinetics” Structure 28, 371-377 (2020). doi: 10.1016/j.str.2020.01.001. PMC7213800.

February 13, 2020/by David Anderson

F. Wu, L. Yang, K. Hang, M. Laursen, L. Wu, G.W. Han, Q. Ren, N.K. Roed, G. Lin, M.A. Hanson, H. Jiang, M.W. Wang, S. Reedtz-Runge, G. Song, R.C. Stevens “Full-length human GLP-1 receptor structure without orthosteric ligands” Nat. Commun. 11, 1272 (2020). doi: 10.1038/s41467-020-14934-5. PMC7062719.

February 13, 2020/by David Anderson

D. Xue, L. Ye, J. Zheng, Y. Wu, X. Zhang, Y. Xu, T. Li, R.C. Stevens, F. Xu, M. Zhuang, S. Zhao, F. Zhao, H. Tao “The structure based traceless specific fluorescence labeling of the smoothened receptor” Org. Biomol. Chem. 17, 6136-6142 (2019). doi: 10.1039/c9ob00654k.

February 13, 2019/by David Anderson
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Yang Yue, Lier Liu, Li-Jie Wu, Yiran Wu, Ling Wang, Fei Li, Junlin Liu, Gye-Won Han, Bo Chen, Xi Lin, Rebecca L Brouillette, Émile Breault, Jean-Michel Longpré, Songting Shi, Hui Lei, Philippe Sarret, Raymond C Stevens, Michael A Hanson, Fei Xu “Structural insight into apelin receptor-G protein stoichiometry” Nat Struct Mol Biol. 2022 Jul;29(7):688-697. doi: 10.1038/s41594-022-00797-5. Epub 2022 Jul 11.

December 6, 2022/by eallison

C. Martin, L.E. Gimenez, S.Y. Williams, Y. Jing, Y. Wu, C. Hollanders, O. Van der Poorten, S. Gonzalez, K. Van Holsbeeck, S. Previti, A. Lamouroux, S. Zhao, D. Tourwe, R.C. Stevens, R.D. Cone, S. Ballet “Structure based design of melanocortin 4 receptor ligands based on the SHU-9119-hMC4R cocrystal structure.” J. Med. Chem. 64, 357-369 (2021). doi: 10.1021/acs.jmedchem.0c01620.

February 13, 2021/by David Anderson

J. Singla, K.L. White, R.C. Stevens, F. Abler “Assessment of scoring functions to rank the quality of 3D subtomogram clusters from cryo-electron tomography” J. Struct. Biol. Online 19 Mar (2021). doi: 10.1016/j.jsb.2021.107727.

February 13, 2021/by David Anderson

Z. Wang, T. Gurlo, A.V. Matveyenko, D. Elashoff, P. Wang, M. Rosenberger, J.A. Junge, R.C. Stevens, K.L. White, S.E. Fraser, P.C. Butler “Live-cell imaging of glucose-induced metabolic coupling of β and α cell metabolism in health and type 2 diabetes” Commun. Biol. 4, 594 (2021). doi: 10.1038/s42003-021-02113-1.

February 13, 2021/by David Anderson

F. Zhao, C. Zhang, Q. Zhou, K. Hang, X. Zou, Y. Chen, F. Wu, Q. Rao, A. Dai, W. Yin, D.D. Shen, Y. Zhang, T. Xia, R.C. Stevens, H.E. Xu, D. Yang, L. Zhao, M.W. Wang “Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.” Elife 10, e68719 (2021). doi: 10.7554/eLife.68719.

February 13, 2021/by David Anderson

R. Lamichhane, J.J. Liu, K.L. White, V. Katritch, R.C. Stevens, K. Wüthrich, D.P. Millar “Biased signaling in the G-protein-coupled receptor β2AR is governed by conformational exchange kinetics” Structure 28, 371-377 (2020). doi: 10.1016/j.str.2020.01.001. PMC7213800.

February 13, 2020/by David Anderson

F. Wu, L. Yang, K. Hang, M. Laursen, L. Wu, G.W. Han, Q. Ren, N.K. Roed, G. Lin, M.A. Hanson, H. Jiang, M.W. Wang, S. Reedtz-Runge, G. Song, R.C. Stevens “Full-length human GLP-1 receptor structure without orthosteric ligands” Nat. Commun. 11, 1272 (2020). doi: 10.1038/s41467-020-14934-5. PMC7062719.

February 13, 2020/by David Anderson

J. Yu, L.E. Gimenez, C.C. Hernandez, Y. Wu, A.H. Wein, G.W. Han, K. McClary, S.R. Mittal, K. Burdsall, B. Stauch, L. Wu, S.N. Stevens, A. Peisley, S.Y. Williams, V. Chen, G.L. Millhauser, S. Zhao, R.D. Cone, R.C. Stevens “Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding” Science 368, 428-433 (2020). online 24 April 2020. doi: 10.1126/science.aaz8995. PMC7567314.

February 13, 2020/by David Anderson

M. Audet, K. Villers, J. Velasquez, M. Chu, C. Hanson, R.C. Stevens “Small-scale approach for precrystallization screening in GPCR X-ray crystallography” Nat. Protoc. 15, 144-160 (2020). doi: 10.1038/s41596-019-0259-y.

February 13, 2020/by David Anderson

B. Stauch, L.C. Johansson, J.D. McCorvy, N. Patel, G.W. Han, X.P. Huang, C. Gati, A. Batyuk, S.T. Slocum, A. Ishchenko, W. Brehm, T.A. White, N. Michaelian, C. Madsen, L. Zhu, T.D. Grant, J.M. Grandner, A. Shiriaeva, R.H.J. Olsen, A.R. Tribo, S. Yous, R.C. Stevens, U. Weierstall, V. Katritch, B.L. Roth, W. Liu, V. Cherezov “Structural basis of ligand recognition at the human MT1 melatonin receptor” Nature 569, 289-292 (2019). doi: 10.1038/s41586-019-1141-3. PMC6696938.

February 13, 2019/by David Anderson
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T. Hua, K. Vemuri, M. Pu, L. Qu, G.W. Han, Y. Wu, S. Zhao, W. Shui, S. Li, A. Korde, R.B. Laprairie, E.L. Stahl, J.-H. Ho, N. Zvonok, H. Zhou, I. Kufareva, B. Wu, Q. Zhao, M.A. Hanson, L.M. Bohn, A. Makriyannis, R.C. Stevens, Z.-J. Liu “Crystal structure of the human cannabinoid receptor CB1” Cell 167, 750-762 (2016). PMC5322940.

February 13, 2016/by David Anderson

M.T. Eddy, T. Didenko, R.C. Stevens, K. Wüthrich “2-Adrenergic receptor conformational response to fusion protein in the third intracellular loop” Structure 24, 1-8 (2016). PMC5144828.

February 13, 2016/by David Anderson

Y. Zheng, L. Qin, N.V. Ortiz Zacarias, H. de Vries, G.W. Han, M. Gustavsson, M. Dabros, C. Zhao, R. Cherney, P. Carter, D. Stamos, R. Abagyan, V. Cherezov, R.C. Stevens, A.P. IJzerman, L.H. Heitman, A. Tebben, I. Kufareva, T.M. Handel “Structure of CC Chemokine Receptor 2 with Orthosteric and Allosteric Antagonists” Nature 540, 458-461 (2016). PMC5159191.

February 13, 2016/by David Anderson

D. Yang, C. de Graaf, L. Yang, G. Song, A. Dai, X. Cai, Y. Feng, S. Reedtz-Runge, M.A. Hanson, H. Yang, H. Jiang, R.C. Stevens, M.W. Wang “Structural determinants of binding the seven-transmembrane domain of the glucagon-like peptide-1 receptor” J. Biol. Chem. 291, 12991-13004 (2016). PMC4933217.

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February 13, 2016/by David Anderson

X.E. Zhou, X. Gao, A. Barty, Y. Kang, Y. He, W. Liu, A. Ishchenko, T.A. White, O. Yefanov, G.W. Han, Q. Xu, P.W. de Waal, K.M. Suino-Powell, S. Boutet, G.J. Williams, M. Wang, D. Li, M. Caffrey, H.N. Chapman, J.C. Spence, P. Fromme, U. Weierstall, R.C. Stevens, V. Cherezov, K. Melcher, H.E. Xu “X-ray laser diffraction structure determination of the rhodopsin-arrestin complex” Sci. Data 3, 160021 (2016). PMC4828943.

February 13, 2016/by David Anderson

X. Lv, J. Liu, Q. Shi, Q. Tan, D. Wu, J.J. Skinner, A.L. Walker, L. Zhao, X. Gu, N. Chen, L. Xue, P. Si, L. Zhang, Z. Wang, V. Katritch, Z.J. Liu, R.C. Stevens “In vitro expression and analysis of the 826 human G protein-coupled receptors” Protein Cell 7, 325-337 (2016). PMC4853319.

February 13, 2016/by David Anderson

S. Yuan, H.C. Chan, H. Vogel, S. Filipek, R.C. Stevens, K. Palczewski “The molecular mechanisms of P2Y1 receptor activation” Angew. Chem. Int. Ed. Engl. 55, 10331-10335 (2016). PMC4996126.

February 13, 2016/by David Anderson

A. Batyuk, L. Galli, A. Ishchenko, G.W. Han, C. Gati, P.A. Popov, M.Y. Lee, B. Stauch, T.A. White, A. Barty, A. Aquila, M.S. Hunter, M. Liang, S. Boutet, M. Pu, Z.J. Liu, G. Nelson, D. James, C. Li, Y. Zhao, J.C. Spence, W. Liu, P. Fromme, V. Katritch, U. Weierstall, R.C. Stevens, V. Cherezov “Native phasing of x-ray free-electron laser data for a G protein-coupled receptor” Sci. Adv. 2, e1600292 (2016). PMC5035125.

February 13, 2016/by David Anderson

X. Zhang, R.C. Stevens, F. Xu. “The importance of ligands for G-protein-coupled receptor stability” Trends Biochem. Sci. 40, 79-87 (2015).

February 13, 2015/by David Anderson

C. O’Connor, K.L. White, N. Donescu, T. Didenko, B.L. Roth, G. Czaplicki, R.C. Stevens, K. Wüthrich, A. Milon. “NMR structure and dynamics of the agonist dynorphin peptide bound to the kappa opioid receptor” Proc. Natl. Acad. Sci. USA 122, 11852-7 (2015). PMC4586840.

February 13, 2015/by David Anderson
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I. Kufareva, M. Rueda, V. Katritch, participants of GPCR Dock 2010, R.C. Stevens, R. Abagyan. “Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment” Structure 19, 1108-1126 (2011). PMC3154726.

February 13, 2011/by David Anderson

A.A. Thompson, J.J. Liu, E. Chun, D. Wacker, H. Wu, V. Cherezov, R.C. Stevens. “GPCR stabilization using bicelle-like architecture of mixed sterol-detergent micelles” Methods 55, 310-317 (2011). PMC3264755.

February 13, 2011/by David Anderson

F. Xu, W. Liu, M.A. Hanson, R.C. Stevens, V. Cherezov “Development of an automated high throughput LCP-FRAP assay to guide membrane protein crystallization in lipid mesophases” Cryst Growth Des 11, 1193-1201 (2011). PMC3108193.

February 13, 2011/by David Anderson

F. Xu, H. Wu, V. Katritch, G.W. Han, K.A. Jacobson, Z.-G. Gao, V. Cherezov, R.C. Stevens “Structure of an agonist-bound human A2A adenosine receptor” Science 332, 322-327 (2011). PMC3086811.

February 13, 2011/by David Anderson

T. Shimamura, M. Shiroishi, S. Weyand, H. Tsujimoto, G. Winter, V. Katritch, R. Abagyan, V. Cherezov, W. Liu, G.W. Han, T. Kobayashi, R.C. Stevens, S. Iwata. “Structure of the human histamine H1 receptor in complex with doxepin” Nature 475, 65-70 (2011). PMC3131495.

February 13, 2011/by David Anderson

C. de Graaf, A.J. Kooistra, H.F. Vischer, V. Katritch, M. Kuijer, M. Shiroshi, S. Iwata, T. Shimamura, R.C. Stevens, I.J.P. de Esch, R. Leurs. “Crystal structure-based virtual screening for novel fragment-like ligands of the human histamine H1 receptor” J Med. Chem. 54, 8195-8206 (2011). PMC3228891.

February 13, 2011/by David Anderson

W. Liu, M.A. Hanson, R.C. Stevens, V. Cherezov. “LCP-Tm: an assay to measure and understand stability of membrane proteins in a membrane environment” Biophys. J. 98, 1539-1548 (2010). PMC2856142.

February 13, 2010/by David Anderson

V. Cherezov, E. Abola, R.C. Stevens “Toward drug design: Recent progress in the structure determination of GPCRs, a membrane protein family with high potential as pharmaceutical targets” Methods Mol. Biol. 654, 141-168 (2010). PMC2973844.

February 13, 2010/by David Anderson

C.G. Tate, R.C. Stevens “Growth and excitement in membrane protein structural biology” Curr. Opin. Struct. Biol. 20, 399-400 (2010).

February 13, 2010/by David Anderson

F. Siu, R.C. Stevens “RAMP-ing up Class B GPCR ECD structural coverage” Structure 18, 1067-1068 (2010).

February 13, 2010/by David Anderson
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G. Snell, C. Cork, R. Nordmeyer, E. Cornell, G. Meigs, D. Yegian, J. Jaklevic, J. Jin, R.C. Stevens, T. Earnest “Automated sample mounting and alignment system for biological crystallography at a synchrotron source” Structure 12, 537-545 (2004).

February 13, 2013/by David Anderson

K.E. Goodwill, M.G. Tennant, R.C. Stevens “High-throughput X-ray crystallography for structure-based drug design” Drug Disc. Today 6, S113-8 (2001).

February 13, 2011/by David Anderson

D.C. Carter, P. Rhodes, D.E. McRee, L. Tari, D.R. Dougan, G. Snell, E. Abola, R.C. Stevens “Reduction in diffuse-convective disturbances in nanovolume protein crystallization experiments” J. Appl. Crystallogr. 38, 87-90 (2005).

February 13, 2005/by David Anderson

R. Page, R.C. Stevens “Crystallization data mining in structural genomics: using positive and negative results to optimize protein crystallization screens.” Methods 34, 373-389 (2004).

February 13, 2004/by David Anderson

M. Bern, D. Goldberg, R.C. Stevens, P. Kuhn “Automatic classification of protein crystallization images using a curve tracking algorithm” J. Appl. Cryst. 37, 279-287 (2004).

February 13, 2004/by David Anderson

R. Page, K. Moy, E.C. Sims, J. Velasquez, B. McManus, C. Grittini, T.L. Clayton, R.C. Stevens “Scalable high-throughput micro-expression device for recombinant proteins” BioTechniques 37, 364-370 (2004).

February 13, 2004/by David Anderson

D. Hosfield, J. Palan, M. Hilgers, D. Scheibe, D. McRee, R.C. Stevens “A fully integrated protein crystallization platform for small molecule drug discovery” J. Struct. Biol. 142, 207-217, (2003).

February 13, 2003/by David Anderson

R.C. Stevens “The cost and value of three-dimensional protein structure” Drug Disc. World 4, 35-48 (2003).

February 13, 2003/by David Anderson

B.D. Santarsiero, D.T. Yegian, C.C. Lee, G. Spraggon, J. Gu, D. Scheibe, D.C. Uber, E.W. Cornell, R.A. Nordmeyer, W.F. Kolbe, J. Jin, A.L. Jones, J.M. Jaklevic, P. G. Schultz, R.C. Stevens “An approach to rapid protein crystallization using nanodroplets” J. Appl. Crystallogr. 35, 278-281 (2002).

February 13, 2002/by David Anderson

P. Kuhn, K. Wilson, M.G. Patch, R.C. Stevens “The genesis of high-throughput structure-based drug discovery using protein crystallography” Curr. Opin. Chem. Biol. 6, 704-710 (2002).

February 13, 2002/by David Anderson
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