Comparison of Crystal Structures of Human Androgen Receptor Ligand-Binding Domain Complexed with Various Agonists Reveals Molecular Determinants Responsible for Binding Affinity
Open accessAbstract
Androgens exert their effects by binding to the highly specific androgen receptor (AR). In addition to natural potent androgens, AR binds a variety of synthetic agonist or antagonist molecules with different affinities. To identify molecular determinants responsible for this selectivity, we have determined the crystal structure of the human androgen receptor ligand-binding domain (hARLBD) in complex with two natural androgens, testosterone (Testo) and dihydrotestosterone (DHT), and with an androgenic steroid used in sport doping, tetrahydrogestrinone (THG), at 1.64, 1.90, and 1.75 A resolution, respectively. Comparison of these structures first highlights the flexibility of several residues buried in the ligand-binding pocket that can accommodate a variety of ligand structures. As expected, the ligand structure itself (dimension, presence, and position of unsaturated bonds that influence the geometry of the steroidal nucleus or the electronic properties of the neighboring atoms, etc.) determines the number of interactions it can make with the hARLBD. Indeed, THG--which possesses the highest affinity--establishes more van der Waals contacts with the receptor than the other steroids, whereas the geometry of the atoms forming electrostatic interactions at both extremities of the steroid nucleus seems mainly responsible for the higher affinity measured experimentally for DHT over Testo. Moreover, estimation of the ligand-receptor interaction energy through modeling confirms that even minor modifications in ligand structure have a great impact on the strength of these interactions. Our crystallographic data combined with those obtained by modeling will be helpful in the design of novel molecules with stronger affinity for the AR.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Molecular docking used PDB entries 3OLL, 3UUD and 2AM9 for ERβ, ERα and AR, respectively, selected as ligand-bound crystal structures to allow ligand docking into the ligand-binding site.
“In these experiments, the protein data bank (PDB) entries 3OLL, 3UUD and 2AM9 were used for ERβ, ERα and AR, respectively [84,85,86]. These crystal structures were specifically selected as they are in ligand-bound states and therefore their conformations would allow ligand docking into the ligand-binding site.”
From Phytoecdysteroids and Anabolic Effect of Atriplex dimorphostegia: UPLC-PDA-MS/MS Profiling, In Silico and In Vivo Models (2023) · cites this paper as [84]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PROCHECK: a program to check the stereochemical quality of protein structures
Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. (1993) · Journal of Applied Crystallography · doi:10.1107/s0021889892009944 · Cited by 24,581 · see citing works
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,299 · see citing works
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,671 · see citing works
MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures
Kraulis, P. J. (1991) · Journal of Applied Crystallography · doi:10.1107/s0021889891004399 · Cited by 14,011 · see citing works
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
Dewar, M. J., Zoebisch, E., Healy, E. F., & Stewart, J. (1985) · Journal of the American Chemical Society · doi:10.1021/ja00299a024 · Cited by 11,560 · see citing works
The nuclear receptor superfamily: the second decade
Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schütz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90199-x · Cited by 6,964 · see citing works
LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions
Wallace, A. C., Laskowski, R. A., & Thornton, J. M. (1995) · Protein Engineering Design and Selection · doi:10.1093/protein/8.2.127 · Cited by 5,705 · see citing works
AMoRe: an automated package for molecular replacement
Navaza, J. (1994) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767393007597 · Cited by 4,941 · see citing works
A new force field for molecular mechanical simulation of nucleic acids and proteins
Weiner, S. J., Kollman, P. A., Case, D. A., Singh, U. C., Ghio, C., Alagona, G., Profeta, S., & Weiner, P. K. (1984) · Journal of the American Chemical Society · doi:10.1021/ja00315a051 · Cited by 4,641 · see citing works
Water: A Comprehensive Treatise
Franks, F. (1979) · Springer eBooks · doi:10.1007/978-1-4684-8018-4 · Cited by 4,065 · see citing works
Free R value: a novel statistical quantity for assessing the accuracy of crystal structures
Brünger, A. T. (1992) · Nature · doi:10.1038/355472a0 · Cited by 3,877 · see citing works
Espinosa, E., Molins, E., & Lecomte, C. (1998) · Chemical Physics Letters · doi:10.1016/s0009-2614(98)00036-0 · Cited by 3,617 · see citing works
Kabsch, W. (1993) · Journal of Applied Crystallography · doi:10.1107/s0021889893005588 · Cited by 3,562 · see citing works
Androgen Receptor in Prostate Cancer
Heinlein, C. A., & Chang, C. (2004) · Endocrine Reviews · doi:10.1210/er.2002-0032 · Cited by 1,780 · see citing works
Monte Carlo-minimization approach to the multiple-minima problem in protein folding.
Li, Z., & Scheraga, H. A. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.19.6611 · Cited by 1,475 · see citing works
Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives*
Quigley, C. A., Bellis, A. D., Marschke, K. B., Awady, M. K. E., Wilson, E. M., & French, F. S. (1995) · Endocrine Reviews · doi:10.1210/edrv-16-3-271 · Cited by 1,436 · see citing works
Mutation of the Androgen-Receptor Gene in Metastatic Androgen-Independent Prostate Cancer
Taplin, M., Bubley, G. J., Shuster, T. D., Frantz, M. E., Spooner, A. E., Ogata, G. K., Keer, H. N., & Balk, S. P. (1995) · New England Journal of Medicine · doi:10.1056/nejm199505253322101 · Cited by 1,243 · see citing works
Principles for modulation of the nuclear receptor superfamily
Gronemeyer, H., Gustafsson, J.-Å., & Laudet, V. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1551 · Cited by 1,228 · see citing works
Biological Actions of Androgens
MOORADIAN, A. D., MORLEY, J. E., & KORENMAN, S. G. (1987) · Endocrine Reviews · doi:10.1210/edrv-8-1-1 · Cited by 1,080 · see citing works
A canonical structure for the ligand-binding domain of nuclear receptors
Wurtz, J., Bourguet, W., Renaud, J., Vivat, V., Chambon, P., Moras, D., & Gronemeyer, H. (1996) · Nature Structural Biology · doi:10.1038/nsb0196-87 · Cited by 986 · see citing works
Veldscholte, J., Ris‐Stalpers, C., Kuiper, G. G. J. M., Jenster, G. W., Berrevoets, C., Claassen, E., van Rooij, H. C. J., Trapman, J., Brinkmann, A. O., & Mulder, E. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)80067-1 · Cited by 945 · see citing works
Atomic structure of progesterone complexed with its receptor
Williams, S. P., & Sigler, P. B. (1998) · Nature · doi:10.1038/30775 · Cited by 659 · see citing works
Structural Evidence for Ligand Specificity in the Binding Domain of the Human Androgen Receptor
Matias, P. M., Donner, P., Coelho, R., Thomaz, M., Peixoto, C., Macedo, S., Otto, N., Joschko, S., Scholz, P., Wegg, A., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004571200 · Cited by 608 · see citing works
Kaplan, W. (2001) · Briefings in Bioinformatics · doi:10.1093/bib/2.2.195 · Cited by 524 · see citing works
Jenster, G., van der Korput, H. A. G. M., van Vroonhoven, C., van der Kwast, T. H., Trapman, J., & Brinkmann, A. O. (1991) · Molecular Endocrinology · doi:10.1210/mend-5-10-1396 · Cited by 523 · cited 2× · see citing works
“Like the other NRs, it is constituted by three main functional domains: a variable N-terminal domain (NTD), a highly conserved DNA-binding domain (DBD), and a conserved ligand-binding domain (LBD) (Jenster et al. 1991).”
BackgroundSack, J. S., Kish, K. F., Wang, C., Attar, R. M., Kiefer, S. E., An, Y., Wu, G. Y., Scheffler, J. E., Salvati, M. E., Krystek, S. R., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081565498 · Cited by 491 · see citing works
Structural basis for antagonism and resistance of bicalutamide in prostate cancer
Bohl, C. E., Gao, W., Miller, D. D., Bell, C. E., & Dalton, J. T. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500381102 · Cited by 426 · see citing works
Roy, A. K., Lavrovsky, Y., Song, C., Chen, S., Jung, M. H., Velu, N., Bi, B., & Chatterjee, B. (1998) · Vitamins and hormones · doi:10.1016/s0083-6729(08)60938-3 · Cited by 412 · see citing works
Current Concepts in Anabolic-Androgenic Steroids
Evans, N. A. (2004) · The American Journal of Sports Medicine · doi:10.1177/0363546503262202 · Cited by 378 · see citing works
Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.
Gaddipati, J. P., McLeod, D. G. R., Heidenberg, H. B., Sesterhenn, I. A., Finger, M. J., Moul, J. W., & Srivastava, S. (1994) · PubMed · Cited by 363 · see citing works
He, B., Gampe, R. T., Kole, A. J., Hnat, A. T., Stanley, T. B., An, G., Stewart, E. L., Kalman, R. I., Minges, J. T., & Wilson, E. M. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.09.036 · Cited by 291 · see citing works
Tetrahydrogestrinone: discovery, synthesis, and detection in urine
Catlin, D. H., Sekera, M. H., Ahrens, B. D., Starcevic, B., Chang, Y., & Hatton, C. K. (2004) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.1495 · Cited by 260 · see citing works
Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface
Hur, E., Pfaff, S. J., Payne, E. S., Grøn, H., Buehrer, B. M., & Fletterick, R. J. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020274 · Cited by 235 · see citing works
Structural Basis for Accommodation of Nonsteroidal Ligands in the Androgen Receptor
Bohl, C. E., Miller, D. D., Chen, J., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507464200 · Cited by 210 · see citing works
Estébanez‐Perpiñá, E., Moore, J. M. R., Mar, E., Delgado-Rodrigues, E., Nguyen, P. T., Baxter, J. D., Buehrer, B. M., Webb, P., Fletterick, R. J., & Guy, R. K. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407046200 · Cited by 164 · see citing works
Androgen resistance due to mutation of the androgen receptor.
Pinsky, L., Trifiro, M. A., Kaufman, M., Beitel, L. K., Mhatre, A. N., Kazemi‐Esfarjani, P., Sabbaghian, N., Lumbroso, R., Alvarado, C., & Vasiliou, M. (1992) · PubMed · Cited by 127 · see citing works
Specific Recognition of Androgens by Their Nuclear Receptor
Poujol, N., Wurtz, J., Tahiri, B., Lumbroso, S., Nicolas, J., Moras, D., & Sultan, C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001999200 · Cited by 122 · see citing works
Coactivators and corepressors as mediators of nuclear receptor function: an update.
Jenster, G. (1998) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(98)00145-2 · Cited by 122 · see citing works
The androgen receptor A mediator of diverse responses
Chang, C. (1996) · Frontiers in bioscience · doi:10.2741/a116 · Cited by 104 · see citing works
Prediction of loop geometries using a generalized born model of solvation effects
Rapp, C. S., & Friesner, R. A. (1999) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(19990501)35:2 · Cited by 103 · see citing works
Androgen Receptor in Human Skin Cytosol*
Mowszowicz, I., IRENE, M., WRIGHT, F., et al. (1981) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-52-2-338 · Cited by 93 · see citing works
Labrie, F., Candas, B., Gomez, J., et al. (2002) · Urology · doi:10.1016/s0090-4295(02)01639-4 · Cited by 89 · see citing works
Self-citationMatias, P. M., Carrondo, M. A., Coelho, R., Thomaz, M., Zhao, X.-Y., Wegg, A., Crusius, K., Egner, U., & Donner, P. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm011072j · Cited by 86 · see citing works
Tetrahydrogestrinone Is a Potent Androgen and Progestin
Death, A. K., McGrath, K. C. Y., Kazlauskas, R., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0033 · Cited by 85 · see citing works
Zhorov, B. S., & Bregestovski, P. D. (2000) · Biophysical Journal · doi:10.1016/s0006-3495(00)76729-4 · Cited by 80 · see citing works
Bellis, A. D., Quigley, C., Cariello, N. F., et al. (1992) · Molecular Endocrinology · doi:10.1210/mend.6.11.1480178 · Cited by 68 · see citing works
Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid
Labrie, F., Luu-The, V., Calvo, E. L., et al. (2005) · Journal of Endocrinology · doi:10.1677/joe.1.05997 · Cited by 50 · see citing works
Self-citationDawood, M. Y., Obasiolu, C., Ramos, J., et al. (1997) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(97)70504-0 · Cited by 35 · see citing works
Ris-Stalpers, C., Verleun-Mooijman, M. C. T., Trapman, J., et al. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.2231 · Cited by 33 · see citing works
Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome
Chávez, B. A., Méndez, J. P., Ulloa‐Aguirre, A., Larrea, F., & Vilchis, F. (2001) · Journal of Human Genetics · doi:10.1007/s100380170021 · Cited by 32 · see citing works
Bilateral testicular tumors in androgen insensitivity syndrome
Sakai, N., Yamada, T., Asao, T., et al. (2000) · International Journal of Urology · doi:10.1046/j.1442-2042.2000.00215.x · Cited by 31 · see citing works
Jasuja, R., Catlin, D. H., Miller, A., Chang, Y., Herbst, K. L., Starcevic, B., Artaza, J. N., Singh, R., Datta, G. D., Sarkissian, A., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0448 · Cited by 31 · see citing works
Theory of Hydrogen Bonding in Water
Rao, C. N. R. (1972) · Springer eBooks · doi:10.1007/978-1-4684-8334-5_3 · Cited by 30 · see citing works
Gerber, N. C., Lowman, H. B., Artis, D. R., & Eigenbrot, C. W. (2000) · Proteins Structure Function and Bioinformatics · doi:10.1002/(sici)1097-0134(20000301)38:4 · Cited by 23 · see citing works
Zhorov, B. S. (1982) · Journal of Structural Chemistry · doi:10.1007/bf00746185 · Cited by 21 · see citing works
Bellis, A. D. (1992) · Molecular Endocrinology · doi:10.1210/me.6.11.1909 · Cited by 21 · see citing works
Harris, S. E., Harris, M. A., Rong, Z. X., et al. (1991) · Springer eBooks · doi:10.1007/978-1-4615-3704-5_35 · Cited by 12 · see citing works
Blanchet, J., Lin, S., & Zhorov, B. S. (2005) · Biochemistry · doi:10.1021/bi047553x · Cited by 9 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Ecdysteroids: A novel class of anabolic agents?
Parr, M., Botrè, F., Naß, A., Hengevoss, J., Diel, P., & Wolber, G. (2014) · Biology of Sport · doi:10.5604/20831862.1144420 · Cited by 95 · see citing works
Nordquist, E. B., Zhao, M., Kumar, A., & MacKerell, A. D. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c01189 · Cited by 15 · see citing works
Zaghloul, E., Handousa, H., Singab, A. N. B., Elmazar, M. M., Ayoub, I. M., & Swilam, N. (2023) · Plants · doi:10.3390/plants12010206 · Cited by 11 · see citing works
- Authors
- Pereira de Jésus‐Tran, K., Côté, P., Cantin, L., Blanchet, J., Labrie, F., & Breton, R.
- Affiliations
- Centre hospitalier de l'Université Laval (CA)
- Corresponding author
- Breton, Rock
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2006-05
- Volume
- 15
- Issue
- 5
- Pages
- 987-999
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC2242507
- OpenAlex
- W2052420006
- Cited by
- 278
- References
- 60
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 28 · 2023: 16 · 2022: 16 · 2021: 16 · 2020: 10 · 2019: 20 · 2018: 16 · 2017: 12 · 2016: 20 · 2015: 11 · 2014: 17 · 2013: 17 · 2012: 8
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- androgen receptor, ligand-binding domain, testosterone, dihydrotestosterone, binding affinity, ligand-receptor interactions, electrostatic interactions, van der Waals contacts, steroid structure, receptor-ligand complex structure
- MeSH terms
- Androgen Antagonists, Androgens, Binding Sites, Crystallization, Gestrinone, Humans, Hydrogen Bonding, Ligands, Protein Binding, Receptors, Androgen, Dihydrotestosterone, Testosterone, Molecular Structure, Protein Structure, Tertiary, Crystallography, X-Ray, Multiprotein Complexes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
