2016 - RCSB · 2016-01-20 · 2016-calendar.indd 7 7/16/15 10:58 AM The drug carbidopa (Lodosyn; highlighted in pink) is used together with levodopa (in blue) to manage the symptoms

2016 Calendar

A Year in Protein-Drug Complexes

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2016-calendar.indd 1 7/16/15 10:58 AM

Vitamin D (yellow) binds to receptors in its target cells, controlling expression of many protein-encoding genes involved in calcium transport and utilization. The receptor is composed of two domains: one that binds to the hormone (orange and red) and another that binds to DNA (blue). It pairs up with a structurally-similar protein, 9-cis retinoic acid receptor (RXR, aqua), and together they bind to the DNA, activating gene expression in some cases and repressing it in others.

2016-calendar.indd 2 7/16/15 10:58 AM

DECEMBER 2015

Su Mo Tu We Th Fri Sa

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18 19

20 21 22 23 24 25 26

27 28 29 30 31

FEBRUARY 2016


1 2 3 4 5 6

7 8 9 10 11 12 13

14 15 16 17 18 19 20

21 22 23 24 25 26 27

28 29

3

1 2

4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30

JANUARY 2016

Sunday Monday Tuesday Wednesday Thursday Friday Saturday

New Year’s Day

Martin Luther King Day

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31

2016-calendar.indd 3 7/16/15 10:58 AM

The cholesterol-lowering drug atorvastatin (Lipitor) is the world’s top-selling drug of all time. It acts by blocking the active site of HMGR, an enzyme present in the liver that catalyzes the formation of cholesterol.

2016-calendar.indd 4 7/16/15 10:58 AM

JANUARY 2016


1 2

3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30

31

MARCH 2016


1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18 19

20 21 22 23 24 25 26

27 28 29 30 31

FEBRUARY 2016

1 2 3 4 5 6

7 8 9 10 11 12 13

14 15 16 17 18 19 20

21 22 23 24 25 26 27

28 29


Lunar New Year Ash Wednesday

Valentine’s Day Presidents’ Day (US)

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2016-calendar.indd 5 7/16/15 10:58 AM

Penicillin V, a β-lactam antibiotic, is used to treat a number of bacterial infections. It acts by blocking a critical step in cell wall formation when infectious bacteria are dividing.

2016-calendar.indd 6 7/16/15 10:58 AM

FEBRUARY 2016


1 2 3 4 5 6

7 8 9 10 11 12 13

14 15 16 17 18 19 20

21 22 23 24 25 26 27

28 29

APRIL 2016


1 2

3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30

MARCH 2016

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18 19

20 21 22 23 24 25 26

27 28 29 30 31


Easter Sunday Daylight Saving Time (EU)

Daylight Saving Time (US) Pi Day St. Patrick’s Day

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2016-calendar.indd 7 7/16/15 10:58 AM

The drug carbidopa (Lodosyn; highlighted in pink) is used together with levodopa (in blue) to manage the symptoms of Parkinson’s disease caused by a loss of dopamine-producing neurons. In the blood stream, carbidopa protects levodopa from being prematurely converted to dopamine by the enzyme DOPA decarboxylase. Once levodopa crosses the blood-brain barrier, it is converted to dopamine by DOPA decarboxylase, supplementing the dwindling dopamine levels. The chemical structure of carbidopa ensures that it does not readily cross the blood-brain barrier.

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MARCH 2016


1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18 19

20 21 22 23 24 25 26

27 28 29 30 31

MAY 2016


1 2 3 4 5 6 7

8 9 10 11 12 13 14

15 16 17 18 19 20 21

22 23 24 25 26 27 28

29 30 31

APRIL 2016

1 2

3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30


DNA Day

Earth Day Passover (at sundown)

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2016-calendar.indd 9 7/16/15 10:58 AM

Many drug-resistant bacteria use enzymes called β-lactamases to inactivate penicillin-like antibiotics, including amoxicillin. One way to overcome this problem is to prescribe traditional antibiotics in conjunction with another drug that blocks the action of β-lactamase. This structure reveals how one such second agent, clavulanic acid, becomes irreversibly bound to the active site of β-lactamase, thereby ensuring the efficacy of amoxicillin.

Amoxicillin

Clavulanic acid

2016-calendar.indd 10 7/16/15 10:58 AM

APRIL 2016


1 2

3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30

JUNE 2016


1 2 3 4

5 6 7 8 9 10 11

12 13 14 15 16 17 18

19 20 21 22 23 24 25

26 27 28 29 30

MAY 2016

1 2 3 4 5 6 7

8 9 10 11 12 13 14

15 16 17 18 19 20 21

22 23 24 25 26 27 28

29 30 31


Mother’s Day (US)

Memorial Day (US)

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2016-calendar.indd 11 7/16/15 10:58 AM

Nucleoside and non-nucleoside reverse transcriptase inhibitors are anti-HIV-1 drugs that function in different ways. The nucleoside zidovudine (AZT, pink) is incorporated into the nascent DNA strand by the enzyme and blocks further transcription with its 3’-azide modification (blue). Non-nucleoside nevirapine (yellow) binds away from the active site and interacts with neither RNA nor DNA. Its mechanism of action is not yet fully understood.

2016-calendar.indd 12 7/16/15 10:58 AM

MAY 2016


1 2 3 4 5 6 7

8 9 10 11 12 13 14

15 16 17 18 19 20 21

22 23 24 25 26 27 28

29 30 31

JULY 2016


1 2

3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30 31

JUNE 2016

1 2 3 4

5 6 7 8 9 10 11

12 13 14 15 16 17 18

19 20 21 22 23 24 25

26 27 28 29 30


Ramadan begins

Father’s Day (US)

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2016-calendar.indd 13 7/16/15 10:58 AM

Lisinopril, shown here bound to its target Angiotensin Converting Enzyme (ACE), is used to treat high blood pressure or hypertension. ACE produces a chemical that causes arteries to contract, which increases blood pressure. By blocking the action of ACE, lisinopril allows arteries to relax and help the heart pump blood more easily.

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JUNE 2016


1 2 3 4

5 6 7 8 9 10 11

12 13 14 15 16 17 18

19 20 21 22 23 24 25

26 27 28 29 30

AUGUST 2016


1 2 3 4 5 6

7 8 9 10 11 12 13

14 15 16 17 18 19 20

21 22 23 24 25 26 27

28 29 30 31

JULY 2016

1 2

3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30


Independence Day (US) Eid al-Fitr

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31

2016-calendar.indd 15 7/16/15 10:58 AM

Baclofen is a muscle relaxant and antispastic used to treat patients with multiple sclerosis, cerebral palsy, and spinal cord injuries. Baclofen binding to GABAB induces conformational changes, activating signal transduction pathways across the membrane and ultimately producing baclofen’s range of therapeutic effects.

Active State with BaclofenResting State

2016-calendar.indd 16 7/16/15 10:58 AM

JULY 2016


1 2

3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20 21 22 23

24 25 26 27 28 29 30 31

SEPTEMBER 2016


1 2 3

4 5 6 7 8 9 10

11 12 13 14 15 16 17

18 19 20 21 22 23 24

25 26 27 28 29 30

AUGUST 2016

1 2 3 4 5 6

7 8 9 10 11 12 13

14 15 16 17 18 19 20

21 22 23 24 25 26 27

28 29 30 31


rcsb.org

2016-calendar.indd 17 7/16/15 10:58 AM

Ibuprofen (white and red), a popular over-the-counter pain reliever, inhibits the cyclooxygenases used by cells to signal pain and inflammation.

2016-calendar.indd 18 7/16/15 10:58 AM

AUGUST 2016


1 2 3 4 5 6

7 8 9 10 11 12 13

14 15 16 17 18 19 20

21 22 23 24 25 26 27

28 29 30 31

OCTOBER 2016


1

2 3 4 5 6 7 8

9 10 11 12 13 14 15

16 17 18 19 20 21 22

23 24 25 26 27 28 29 30 31

SEPTEMBER 2016

1 2 3

4 5 6 7 8 9 10

11 12 13 14 15 16 17

18 19 20 21 22 23 24

25 26 27 28 29 30


Labor Day (US)

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2016-calendar.indd 19 7/16/15 10:58 AM

Dopamine transporters remove the neurotransmitter dopamine from the gap between adjacent neurons called a synapse. Because dopamine transporters are critical to communication between neurons, they are frequently the target of drugs that affect thought and mood. Antidepressant drugs (such as nortriptyline, shown here) take advantage of this effect by blocking dopamine transporters. Drugs of abuse like cocaine also block the action of these transporters.

2016-calendar.indd 20 7/16/15 10:58 AM

SEPTEMBER 2016


1 2 3

4 5 6 7 8 9 10

11 12 13 14 15 16 17

18 19 20 21 22 23 24

25 26 27 28 29 30

NOVEMBER 2016


1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18 19

20 21 22 23 24 25 26

27 28 29 30

OCTOBER 2016

1

2 3 4 5 6 7 8

9 10 11 12 13 14 15

16 17 18 19 20 21 22

23 24 25 26 27 28 29


Rosh Hashanah (at sundown)

DiwaliDaylight Saving Time ends (EU) Halloween

Columbus Day Yom Kippur (at sundown)

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3130

2016-calendar.indd 21 7/16/15 10:58 AM

In Type 2 Diabetes, the enzyme DPP-4 is responsible for degrading hormones that stimulate the pancreas to release insulin. Sitagliptin (Januvia) blocks the action of DPP-4 to keep these hormones in the blood stream longer than normal, thereby stimulating the pancreas to make more insulin. As a result, blood sugar is better controlled, and sugar-induced damage to eyes, kidneys, blood vessels, and nerves can be prevented.

2016-calendar.indd 22 7/16/15 10:58 AM

OCTOBER 2016


1

2 3 4 5 6 7 8

9 10 11 12 13 14 15

16 17 18 19 20 21 22

23 24 25 26 27 28 29 30 31

DECEMBER 2016


1 2 3

4 5 6 7 8 9 10

11 12 13 14 15 16 17

18 19 20 21 22 23 24

25 26 27 28 29 30 31

NOVEMBER 2016

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18 19

20 21 22 23 24 25 26

27 28 29 30


Daylight Saving Time ends (US) Election Day (US) Veterans Day

Thanksgiving (US)

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2016-calendar.indd 23 7/16/15 10:58 AM

The monoclonal antibody ustekinumab (pink) binds to Interleukin 12 (dark blue) and is a treatment for psoriasis. Only the antigen-binding fragments of antibodies are shown here.

Many proteins are used in the treatment of disease.

The hormone erythropoietin (red), shown bound to erythropoietin receptor (green), is used to treat anemia.

Monoclonal antibodies infliximab (yellow) and adalimumab (aqua) bind to tumor necrosis factor alpha (purple) and are approved for the treatment of arthritis, psoriasis, and Crohn’s disease.

2016-calendar.indd 24 7/16/15 10:58 AM

NOVEMBER 2016


1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18 19

20 21 22 23 24 25 26

27 28 29 30

JANUARY 2017


1 2 3 4 5 6 7

8 9 11 12 13 14

15 16 17 18 19 20 21

22 23 24 25 26 27 28

29 30 31

DECEMBER 2016

1 2 3

4 5 6 7 8 9 10

11 12 13 14 15 16 17

18 19 20 21 22 23 24

25 26 27 28 29 30 31


Christmas Kwanzaa New Year’s Eve

Hanukkah (at sundown)

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2016-calendar.indd 25 7/16/15 10:58 AM

About the Cover

Imatinib, a tyrosine-kinase inhibitor, revolutionized the treatment of chronic myeloid leukemia (CML). It works by blocking the action of the protein BCR-Abl tyrosine kinase, an enzyme created by a chromosomal abnormality. CML cancer cells die when exposed to this drug.

A Year in Protein-Drug Complexes

Proteins are tiny molecular machines. While not visible with the naked eye, their structures and functions can be investigated and understood through various experimental methods. Proteins perform many of the tasks needed to support living cells. Illnesses, such as cancer, can occur when they are prevented from performing their normal jobs. Other ailments are caused when foreign proteins (such as from bacteria or viruses) interfere with ours. Most drugs are small chemicals, even smaller than proteins, that work by binding to target proteins and modifying their actions within our cells. Other drugs are modified proteins that can take the place of improperly operating native proteins.

Some of our most powerful anticancer drugs completely disable an essential molecular machine, without which the cell cannot survive. These drugs kill cancer cells outright. Other drugs, such as cholesterol lowering agents, blunt the action of less-critical proteins to benefit patients.

We know a great deal about how drugs work because scientists in academe and the pharmaceutical industry are able to examine drug-protein complexes at the level of individual atoms. These three-dimensional (3D) atomic structures allow us to see how drugs bind to their protein targets in exquisite detail. Frequently, these structures suggest ways to modify the structure of the drug to better fit the target protein, either to improve efficacy or to reduce the likelihood of side effects.

These structures of proteins and drugs, along with many others, can be explored at the RCSB PDB (rcsb.org).

About the RCSB PDB

RCSB PDB is a vital resource for biological research and education worldwide.

It provides enhanced access to information about the 3D structures of more than 110,000 nucleic acids, proteins, and large molecular machines contained in the Protein Data Bank (PDB) archive.

The RCSB PDB supports the development of standards for the representation, annotation, and validation of these structural data that are collected from different experimental methods. Tools for query, visualization, and analysis of PDB data are developed and made available. An online educational portal is enhanced by online and in-person outreach efforts targeted at promoting a structural view of biology.

RCSB PDB resources are utilized by a variety of researchers, teachers, and students studying biology and its connections to molecular biology, structural biology, computational biology, pharmacology, and more.

Acknowledgements

Thanks to the many people who helped develop this calendar: Luigi Di Costanzo, Sutapa Ghosh, David S. Goodsell, Rachel Kramer Green, Brian Hudson, Yu-He Liang, Ezra Peisach, Irina Persikova, Monica Sekharan, Chenghua Shao, Maria Voigt, Christine Zardecki, and Stephen K. Burley.

ReferencesPDB ID 2hyy S. W. Cowan-Jacob, G. Fendrich, A. Floer-sheimer, P. Furet, J. Liebetanz, G. Rummel, P. Rheinberger, M. Centeleghe, D. Fabbro, P. W. Manley. (2007) Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr 63: 80-93.

PDB ID 1t46 C. D. Mol, D. R. Dougan, T. R. Schneider, R. J. Skene, M. L. Kraus, D. N. Scheibe, G. P. Snell, H. Zou, B. C. Sang, K. P. Wilson. (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 279: 31655-31663.

RCSB PDB is located at Rutgers, The State University of New Jersey and the University of California, San Diego.

RCSB PDB is supported by a grant (DBI-1338415) from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.

RCSB PDB is a member of the Worldwide Protein Data Bank.

Molecular images were created using UCSF Chimera (E. F. Pettersen, T. D. Goddard, C. C. Huang, et al. (2004) Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25: 1605-1612.), PyMOL (The PyMOL Molecular Graphics System, Version 1.7.4 Schrödinger, LLC.), and PMV (M. F. Sanner (1999) Python: A Programming Language for Software Integration and Development. J. Mol. Graphics Mod. 17: 57-61.)

Cover:

2016-calendar.indd 26 7/16/15 10:58 AM

January:EMD-1985 I. Orlov, N. Rochel, D. Moras, B. P. Klaholz. (2012) Structure of the full human RXR/VDR nuclear receptor heterodi-mer complex with its DR3 target DNA. EMBO J 31: 291-300.

PDB ID 1dkf W. Bourguet, V. Vivat, J. M. Wurtz, P. Chambon, H. Gronemeyer, D. Moras. (2000) Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 5: 289-298.

PDB ID 1db1 N. Rochel, J. M. Wurtz, A. Mitschler, B. Klaholz, D. Moras. (2000) The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell 5: 173-179.

PDB ID 1ynw P. L. Shaffer, D. T. Gewirth. (2004) Structural analysis of RXR-VDR interactions on DR3 DNA. J Steroid Biochem Mol Biol 89-90: 215-219.

PDB ID 2nll F. Rastinejad, T. Perlmann, R. M. Evans, P. B. Sigler. (1995) Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375: 203-211.

February:PDB ID 1hwk E. S. Istvan, J. Deisenhofer. (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292: 1160-1164.

March:PDB ID 2ex9 H. Kishida, S. Unzai, D. I. Roper, A. Lloyd, S. Y. Park, J. R. Tame. (2006) Crystal structure of penicillin binding protein 4 (dacB) from Escherichia coli, both in the native form and covalently linked to various antibiotics. Biochemistry 45: 783-792.

April:PDB ID 1js3 P. Burkhard, P. Dominici, C. Borri-Voltattorni, J. N. Jansonius, V. N. Malashkevich. (2001) Structural insight into Parkinson’s disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Biol 8: 963-967.

May:PDB ID 3cg5 L. W. Tremblay, J. E. Hugonnet, J. S. Blanchard. (2008) Structure of the covalent adduct formed between Mycobacterium tuberculosis beta-lactamase and clavulanate. Biochemistry 47: 5312-5316.

June:PDB ID 3v81 K. Das, S. E. Martinez, J. D. Bauman, E. Arnold. (2012) HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism. Nat Struct Mol Biol 19: 253-259.

July:PDB ID 1o86 R. Natesh, S. L. Schwager, E. D. Sturrock, K. R. Acharya. (2003) Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature 421: 551-554.

August:

PDB IDs 4mqe, 4ms4 Y. Geng, M. Bush, L. Mosyak, F. Wang, Q. R. Fan. (2013) Structural mechanism of ligand activation in human GABA(B) receptor. Nature 504: 254-259.

September:PDB ID 4ph9 B. J. Orlando, M. J. Lucido, M. G. Malkowski. (2015) The structure of ibuprofen bound to cyclooxygen-ase-2. J Struct Biol. 189: 62-66.

October:PDB ID 4m48 A. Penmatsa, K. H. Wang, E. Gouaux. (2013) X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature 503: 85-90.

November:PDB ID 1x70 D. Kim, L. Wang, M. Beconi, G. J. Eiermann, M. H. Fisher, H. He, G. J. Hickey, J. E. Kowalchick, B. Leiting, K. Lyons, F. Marsilio, M. E. McCann, R. A. Patel, A. Petrov, G. Scapin, S. B. Patel, R. S. Roy, J. K. Wu, M. J. Wyvratt, B. B. Zhang, L. Zhu, N. A. Thornberry, A. E. Weber. (2005) (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48: 141-151.

December:PDB ID 1cn4 R. S. Syed, S. W. Reid, C. Li, J. C. Cheetham, K. H. Aoki, B. Liu, H. Zhan, T. D. Osslund, A. J. Chirino, J. Zhang, J. Finer-Moore, S. Elliott, K. Sitney, B. A. Katz, D. J. Matthews, J. J. Wendoloski, J. Egrie, R. M. Stroud. (1998) Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 395: 511-516.

PDB ID 4g3y S. Liang, J. Dai, S. Hou, L. Su, D. Zhang, H. Guo, S. Hu, H. Wang, Z. Rao, Y. Guo, Z. Lou. (2013) Structural basis for treating tumor necrosis factor alpha (TNFalpha)-associated diseases with the therapeutic antibody infliximab. J Biol Chem 288: 13799-13807.

PDB ID 3wd5 S. Hu, S. Liang, H. Guo, D. Zhang, H. Li, X. Wang, W. Yang, W. Qian, S. Hou, H. Wang, Y. Guo, Z. Lou. (2013) Comparison of the inhibition mechanisms of adali-mumab and infliximab in treating tumor necrosis factor alpha-associated diseases from a molecular view. J Biol Chem 288: 27059-27067.

PDB ID 3hmx J. Luo, S. J. Wu, E. R. Lacy, Y. Orlovsky, A. Baker, A. Teplyakov, G. Obmolova, G. A. Heavner, H. T. Richter, J. Benson. (2010) Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab. J Mol Biol 402: 797-812.

Back Cover:

PDB IDs 4eyf (Benzylpenicillin, at center), 4ey2 (Methicillin), 4eyl (Meropenem) D. T. King, L. J. Worrall, R. Gruninger, N. C. Strynadka. (2012) New Delhi metallo-beta-lactamase: structural insights into beta-lactam recognition and inhibition. J Am Chem Soc 134: 11362-11365.

PDB ID 3q6x (Ampicillin) H. Zhang, Q. Hao. (2011) Crystal structure of NDM-1 reveals a common beta-lactam hydrolysis mechanism. FASEB J 25: 2574-2582.

PDB ID 4rl2 (Cephalexin) H. Feng, J. Ding, D. Zhu, X. Liu, X. Xu, Y. Zhang, S. Zang, D. C. Wang, W. Liu. (2014) Structural and mechanistic insights into NDM-1 catalyzed hydrolysis of cephalosporins. J Am Chem Soc 136: 14694-14697.

2016-calendar.indd 27 7/16/15 10:58 AM

Antibiotics have saved countless lives, but today antibiotic-resistant strains of bacteria represent a dangerous new global threat. Bacteria that possess the recently characterized NDM-1 metallo-β-lactamase enzyme are particularly worrisome. NDM-1 is unique in that it can inactivate all approved penicillin-like antibiotics. PDB structures reveal how NDM-1 can adjust its shape to inactivate antibiotics, including our most advanced carbapenem antibiotics.

Ampicillin

Methicillin

Cephalexin

Meropenem

2016-calendar.indd 28 7/16/15 10:58 AM

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2016 - RCSB · 2016-01-20 · 2016-calendar.indd 7 7/16/15 10:58 AM The drug carbidopa (Lodosyn; highlighted in pink) is used together with levodopa (in blue) to manage the symptoms