K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site

doi:10.1038/nature22988

. 2017 Jul 20;547(7663):364-368.

doi: 10.1038/nature22988. Epub 2017 Jul 10.

K_2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site

Marco Lolicato¹, Cristina Arrigoni¹, Takahiro Mori², Yoko Sekioka², Clifford Bryant³, Kimberly A Clark¹, Daniel L Minor Jr^{1

4

5

6

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Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, California 941158-9001, USA.
² Ono Pharmaceutical Co. Ltd, Mishima-Gun, Osaka 618-8585, Japan.
³ Small Molecule Discovery Center, University of California, San Francisco, California 93858-2330, USA.
⁴ Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, California 941158-9001, USA.
⁵ California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 941158-9001, USA.
⁶ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California 941158-9001, USA.
⁷ Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

PMID: 28693035
PMCID: PMC5778891
DOI: 10.1038/nature22988

K_2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site

Marco Lolicato et al. Nature. 2017.

. 2017 Jul 20;547(7663):364-368.

doi: 10.1038/nature22988. Epub 2017 Jul 10.

Authors

Marco Lolicato¹, Cristina Arrigoni¹, Takahiro Mori², Yoko Sekioka², Clifford Bryant³, Kimberly A Clark¹, Daniel L Minor Jr^{1

4

5

6

7}

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, California 941158-9001, USA.
² Ono Pharmaceutical Co. Ltd, Mishima-Gun, Osaka 618-8585, Japan.
³ Small Molecule Discovery Center, University of California, San Francisco, California 93858-2330, USA.
⁴ Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, California 941158-9001, USA.
⁵ California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 941158-9001, USA.
⁶ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California 941158-9001, USA.
⁷ Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

PMID: 28693035
PMCID: PMC5778891
DOI: 10.1038/nature22988

Abstract

Polymodal thermo- and mechanosensitive two-pore domain potassium (K_2P) channels of the TREK subfamily generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K_2P channels use a selectivity filter 'C-type' gate as the principal gating site. Despite recent advances, poor pharmacological profiles of K_2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K_2P2.1 (also known as TREK-1) alone and with two selective K_2P2.1 (TREK-1) and K_2P10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402-define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation-π interaction that controls selectivity. Together, our data reveal a druggable K_2P site that stabilizes the C-type gate 'leak mode' and provide direct evidence for K_2P selectivity filter gating.

PubMed Disclaimer

Conflict of interest statement

Competing financial interests statement

M.L. C.A. K.A.C, C.B., and D.L.M. declare no financial interests.

T.M and Y.S. are employees of Ono Pharmaceutical, Co. Ltd.

Figures

**Extended Data Figure 1. K_2P2.1(TREK-1)_cryst function and structure**
a, Exemplar recording from K_2P2.1(TREK-1)_cryst expressed in *Xenopus* oocytes. Current was elicited from a −80mV holding potential followed by a 500 ms ramp from −150 mV to +50 mV. b, K_2P2.1(TREK-1)_cryst potassium selectivity recorded in *Xenopus* oocytes in K⁺/N-methyl-D-glucamine solutions (98.0 mM total) at pH_o= 7.4. Data represent mean ± SEM (n= 4). Dashed gray line represents Nernst equation E_rev=RT/F*log([K⁺]_o/[K⁺]_i), where R and F have their usual thermodynamic meanings, z is equal to 1, and T=23°C, assuming [K⁺]_I = 108.6 mM. c, Exemplar 2F_o-F_c electron density (1.0 σ) for the C-tail region of K_2P2.1(TREK-1)_cryst. Select residues and channel elements are indicated. d, Extracellular view of K_2P2.1(TREK-1)_cryst showing environment of His126 and Ile148 (raspberry). Select residues are labeled. The extracellular proton sensor His126^, is supported by a highly conserved residue, Trp127, and contacts a gain-of-function (GOF) mutant site, Ile148, that interacts with the selectivity filter residue Asn147. This network of physical interactions indicates how changes at His126^, or Ile148 could affect the C-type gate. e, and f, Exemplar L2/L3 lipid electron density for K_2P2.1(TREK-1):ML335. e, 2Fo-Fc, (blue, 1.0 σ) and f, F_o-F_c, (hotpink, 3.0 σ). Chains are colored smudge and light orange. Channel elements and select residues are labeled. g, Crystal lattice packing for K_2P2.1(TREK-1)_cryst showing that the C-tail makes lattice interactions stabilized by a cadmium ion coordinated between His313 of adjacent symmetry mates. Asymmetric unit is colored smudge (chain A) and light orange (chain B). Symmetry related channels are shown in slate (chain A) and cyan (chain B). Insets show the anomalous difference map (5.0σ) and locations of Cd²⁺ ions and their ligands.

**Extended Data Figure 2. K_2P2.1(TREK-1)_cryst modulator binding pocket densities and K_2P2.1(TREK-1)_cryst functional properties**
**a–e**, Exemplar electron densities for the modulator binding pockets. a–c, 2F_o-F_c densities (blue) for a, K_2P2.1(TREK-1):ML335 (1.5 σ), b, K_2P2.1(TREK-1):ML402 (1.0 σ), and c, K_2P 2.1(TREK-1) (1.0 σ). Offset angle for the cation-π interactions for Lys271:ML335 and Lys271:ML402 is shown and adopts an oblique geometry common to cation-π interactions^,. d, and e, F_o-F_c densities (hotpink, 3.0 σ) for d, K_2P2.1(TREK-1):ML335 and e, K_2P2.1(TREK-1):ML402. Final models are shown in all panels and select residues are shown and labeled. f–h, Exemplar current traces for f, K_2P2.1 (TREK-1)_cryst (black) with 40 μM ML335 (yellow orange), g, K_2P2.1 (TREK-1)_cryst (black) with 80 μM ML402 (green), and h, K_2P2.1 (TREK-1) G137I (black) with 80 μM ML335 (blue). i, Dose response curves for K_2P2.1(TREK-1):ML335 (black), EC₅₀=14.3 ± 2.7 μM (n≥5); K_2P2.1 (TREK-1)_cryst:ML335, EC₅₀ = 10.5 ± 2.7 μM (n≥3) (yellow orange) K_2P2.1 (TREK-1)_cryst:ML402, EC₅₀ = 14.9 ± 1.6 μM (n≥3); and K_2P2.1(TREK-1) G137I:ML335 (blue ).

**Extended Data Figure 3. Comparison of K_2P modulator and VGIC antagonist sites**
a, Superposition of the K_2P2.1(TREK-1):ML335 complex (smudge and light orange) with the BacNa_V ‘pore-only’ Na_VMs structure (magenta and warm pink). Bromine site (Br) from labeled sodium channel antagonists is shown as a firebrick sphere. b, Superposition of the pore domains of the K_2P2.1(TREK-1):ML335 complex (smudge and light orange) with the pore domain of the BacNa_V Ca_VAb (5KMD) bound to the inhibitor amlodipine (AMLOD), a site normally occupied by lipid^,. Select residues of the K_2P modulator pocket are shown as sticks and are labeled. Ca_VAb subunits are colored cyan, marine, slate, and dark blue. ML335 (yellow) and amlodipine (cyan) are shown in space filling representation.

**Extended Data Figure 4. K_2P modulator pocket structure and conservation**
Details of a, ML335, and b, ML402 interactions with K_2P2.1(TREK-1). c and d, Representative K_2P channel sequence comparisons for the c, M4 face and d, P1 face. Purple bar and orange shading on sequence identifiers denotes the thermo- and mechanosensitive K_2P2.1(TREK-1) subfamily. Protein secondary structure is marked above the sequences. Selectivity filter region is in red. Residues involved in direct interactions with ML335 and ML402 are orange and marked with an orange asterisk. Conserved positions are highlighted. K_2P2.1(TREK-1) is the mouse protein used for this study. K_2P2.1H(TREK-1) is the human homolog. All other K_2P sequences are human origin. Sequences and identifiers are as follows: K_2P2.1(TREK-1) NP_034737.2; K_2P2.1H(TREK-1), NP_001017424.1; K_2P10.1(TREK-2), NP_612190.1; K_2P4.1(TRAAK), NP_001304019.1; K_2P3.1(TASK-1), NP_002237.1; K_2P9.1(TASK-3), NP_001269463.1; K_2P5.1(TASK-2), NP_003731.1; K_2P1.1(TWIK-1), NP_002236.103812.2; K_2P6.1(TWIK-2), NP_004823.1; K_2P7.1(KCNK7), AAI03812.2; K_2P16.1(TALK-1), NP_001128577.1; K_2P17.1(TALK-2), NP_113648.2; K_2P12.1(THIK-2), NP_071338.1; K_2P12.1(THIK-1), NP_071337.2; K_2P15.1(TASK-5), NP_071753.2; and K_2P18.1(TRESK), NP_862823.1. ‘●’ in K_2P16.1(TALK-1) sequence in ‘c’ denotes the following, non-conserved sequence that was removed to avoid a long alignment gap: NFITPSGLLPSQEPFQTPHGKPESQQIP.

**Extended Data Figure 5. K_2P structure comparisons**
K_2P modulator pocket views colored by B-factor for a, K_2P2.1(TREK-1), b, K_2P2.1(TREK-1):ML335, and c, K_2P2.1(TREK-1):ML402. Bars show B-factor scale.

**Extended Data Figure 6. K_2P structure comparisons**
a, Backbone atom superposition of K_2P2.1(TREK-1) (smudge, up), K_2P2.1(TREK-1):ML335 (yellow, up), K_2P2.1(TREK-1):ML402 (cyan, up), K_2P10.1(TREK-2) (4BW5) (pink, up), K_2P10.1(TREK-2) (4XDJ) (magenta, down), K_2P10.1(TREK-2):Norfluoxetine (4XDK)(violet purple, down), K_2P4.1(TRAAK) (4I9W) (limon, up), K_2P4.1(TRAAK) G124I (4RUE) (marine, down), and K_2P4.1(TRAAK) W262S (4RUF) (lime, down). ‘up’ or ‘down’ denotes M4 conformation. Selectivity filter ions for K_2P2.1(TREK-1) (smudge), K_2P2.1(TREK-1):ML335 (yellow), and K_2P2.1(TREK-1):ML402 (cyan) are shown as spheres. ML335 and ML402 are shown in sticks. Select channel elements are labeled. **b–e,** Superposition showing b, K_2P2.1(TREK-1) chain A (smudge) and chain B (light orange). Sites of GOF mutations, G137I (orange), and Trp275, are indicated. c, K_2P2.1(TREK-1):ML335 chain A (pink) and chain B (deep salmon), d, K_2P2.1(TREK-1):ML402 chain A (cyan) and chain B (deep teal). e, K_2P2.1(TREK-1) chain A (smudge) and chain B (light orange), K_2P10.1(TREK-2) (4BW5) (pink), K_2P10.1(TREK-2) (4XDJ) (magenta), K_2P10.1(TREK-2):Norfluoxetine (4XDK)(violet purple). f, K_2P2.1(TREK-1):ML335 (deep salmon), K_2P4.1(TRAAK) (4I9W) (limon), K_2P4.1(TRAAK) G124I (4RUE) (marine), K_2P4.1(TRAAK) W262S (4RUF) (lime). G124I from K_2P4.1(TRAAK) G124I is shown in sticks. In **b–f**, Phe134, His126, Lys271, Trp275, their equivalents in K_2P10.1(TREK-2), K_2P4.1(TRAAK), and K_2P4.1(TRAAK) G124I, are shown in sticks. ML335, ‘c’, and ML402, **‘d’**, are shown as sticks.

**Extended Data Figure 7. K_2P activator responses**
Exemplar current traces for a, K_2P10.1(TREK-2) (black) with 20 μM ML335 (yellow orange) and b, K_2P10.1(TREK-2) (black) with 20 μM ML402 (cyan). c, Dose response curves for K_2P10.1(TREK-2) with ML335 (EC₅₀ = 5.2 ± 0.5 μM (n>3)) (yellow orange) and ML402 (EC₅₀ = 5.9 ± 1.6 μM (n≥4)(cyan). Exemplar current traces for d, K_2P2.1(TREK-1) K271Q (black) and with 20 μM ML335 (purple). e, K_2P4.1(TREK-1) Q258K (black) and with 50 μM ML335 (orange). f, K_2P2.1(TREK-1) K271Q (black) and with 50 μM ML402 (purple). g, K_2P4.1(TREK-1) Q258K (black) and with 50 μM ML402 (orange). Currents were evoked from *Xenopus* oocytes expressing the indicated channels from a −80 mV holding potential followed by a 500 ms ramp from −150 mV to +50 mV. Compound structures are shown. h, and i, Exemplar current traces for HEK293 cell inside-out patches expressing h, K_2P2.1(TREK-1) and i, K_2P2.1(TREK-1) K271Q to stimulation by 10 μM arachidonic acid (AA) (green). j, Current potentiation measured in HEK cells at 0 mV in response to 10μM AA for K_2P2.1(TREK-1) (n=5) and K_2P2.1(TREK-1) K271Q (n=4). k, Current potentiation measured in *Xenopus* oocytes at 0 mV for K_2P4.1(TRAAK) (white), K_2P2.1(TREK-1) (black), K_2P4.1(TRAAK) Q258K (cyan) and K_2P2.1(TREK-1) K271Q (gray) in response to 10 μM BL-1249, 30 μM ML67-33, and 20 μM ML335. For all experiments (n≥4). Data are mean ± SEM.

**Extended Data Figure 8. K_2P channel patch clamp recordings**
a, Dose response for K_2P2.1(TREK-1) to ML335 (black circles) and ML402 (open circles) measured in HEK293 cells by whole cell patch clamp. EC₅₀ values are 5.2 ± 0.8 μM and 5.9 ± 1.6 μM for ML335 and ML402, respectively (n≥3). b, and c, Representative current traces and voltage-current relationship from HEK293 inside-out patches for expressing b, K_2P4.1(TRAAK) and c, K_2P4.1(TRAAK) G124I elicited by a 350 ms-voltage step protocol from −100 mV to +100 mV in 150 mM K⁺_[out]/150 mM Rb⁺_[in]. d, Rectification coefficients (I_+100mV/I-_100mV) calculated from n≥3 current recordings obtained from the same conditions in ‘b’ and ‘c’.

**Figure 1. K_2P2.1(TREK-1) structures**
a, K_2P2.1(TREK-1)_cryst cartoon (smudge and light orange) smudge subunit extracellular cap domain (CAP), M1–M4 transmembrane helices, C-tail, and V321 are labeled. b, K_2P modulator pocket cutaway. Cutouts display ML335 and ML402 F_o-F_c densities (3.0σ). ML335, ML402, and Selectivity Filter 1 (SF1) are sticks. c, and d, Extracellular views excluding the CAP domain of c, ML335 and d, ML402 binding sites. ML335 and ML402 are space filling. Selectivity filter sidechains are sticks. e, Wire representation comparing K_2P2.1(TREK-1):ML335 (smudge and light orange) and K_2P10.1(TREK-2):norfluoxetine (light pink and magenta) binding sites. K_2P2.1(TREK-1) P1 and P2 are cylinders. ML335 (yellow) and norfluoxetine (NorFx) (red) are space filling. In all panels select residues and channel elements are indicated, and where present, grey lines indicate the membrane.

**Figure 2. K_2P2.1(TREK-1) activator interactions**
Cartoon diagram of a, K_2P2.1(TREK-1):ML335 and b, K_2P2.1(TREK-1):ML402 interactions. Electrostatic and hydrogen bond interactions are black. Cation-π and π-π interactions are grey. c, and d, comparison of K_2P2.1(TREK-1) (smudge) with c, K_2P2.1(TREK-1):ML335 (deep salmon) and d, K_2P2.1(TREK-1):ML402 (cyan).

**Figure 3. K_2P2.1(TREK-1) C-tail and lipid binding sites**
a, K_2P2.1(TREK-1) C-tail. Positively charged residues are blue. S300A and E306A, a site having slight distortion from helical geometry, are magenta. b, K_2P2.1(TREK-1) Electrostatic surface potential. Orange box highlights M1/M2/M4 junction. Cytoplasmic view (left) indicates C-tail positively charged patch. c, Lipids L1, L2, and L3 (cyan and white) shown as space filling. ML335 (yellow) is indicated. Insets show lipid binding pocket details.

**Figure 4. K_2P2.1(TREK-1) activator function**
Exemplar current traces for a, K_2P2.1(TREK-1) (black) with 20 μM ML335 (purple). b, K_2P4.1(TRAAK) (black) with 50 μM ML335 (orange). c, ML335 dose response curves for K_2P2.1(TREK-1) (black), EC₅₀=14.3 ± 2.7 μM (n≥5); K_2P2.1(TREK-1) K271Q (blue filled circles); K_2P4.1(TRAAK) (orange); K_2P4.1(TRAAK) Q258K (green) EC₅₀=16.2 ± 3.0 μM (n≥4); and ML335a: K_2P2.1(TREK-1) (black open triangles). Exemplar current traces for d, K_2P2.1(TREK-1) (black) with 20 μM ML402 (purple). e, K_2P4.1(TRAAK) (black) with 50 μM ML335 (orange). f, ML402 dose response curves for K_2P2.1(TREK-1) (black), EC₅₀=13.7 ± 7.0 μM (n≥3); K_2P2.1(TREK-1) K271Q (blue); K_2P2.1(TREK-1) (blue); K_2P4.1(TRAAK) (orange); K_2P4.1(TRAAK) Q258K (green) EC₅₀=13.6 ± 1.5 μM (n≥3). **g–j,** Exemplar current traces and voltage-current relationships for indicated K_2Ps in HEK293 inside-out patches in 150 mM K⁺_[out]/150 mM Rb⁺_[in] for g, K_2P2.1(TREK-1), h, K_2P2.1(TREK-1) with 5 μM ML335, I, K_2P2.1(TREK-1) with 5 μM ML402, and j, K_2P2.1(TREK-1) G137I. k, Rectification coefficients (I_+100mV/I_–100mV) from recordings (n≥3) made in ‘**g–j’. l,** TREK activation model. Grey lines indicate mobile P1 (tan) and M4 (blue). C-type activators (orange), stabilize the selectivity filter and channel ‘leak mode’. Potassium ions are purple. Gap in arrows indicates current flow intensity. Membrane is grey.

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References

1. Feliciangeli S, Chatelain FC, Bichet D, Lesage F. The family of K channels: salient structural and functional properties. J Physiol. 2014 doi: 10.1113/jphysiol.2014.287268. - DOI - PMC - PubMed
1. Devilliers M, et al. Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nat Commun. 2013;4:2941. doi: 10.1038/ncomms3941. - DOI - PubMed
1. Vivier D, et al. Development of the first Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K+ Channel 1)-selective agonist possessing in vivo anti-nociceptive activity. Journal of medicinal chemistry. 2017 doi: 10.1021/acs.jmedchem.6b01285. - DOI - PubMed
1. Brohawn SG, del Marmol J, MacKinnon R. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science. 2012;335:436–441. doi: 10.1126/science.1213808. 335/6067/436 [pii] - DOI - PMC - PubMed
1. Miller AN, Long SB. Crystal structure of the human two-pore domain potassium channel K2P1. Science. 2012;335:432–436. doi: 10.1126/science.1213274. 335/6067/432 [pii] - DOI - PubMed

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[1] Feliciangeli S, Chatelain FC, Bichet D, Lesage F. The family of K channels: salient structural and functional properties. J Physiol. 2014 doi: 10.1113/jphysiol.2014.287268. - DOI - PMC - PubMed

[2] Feliciangeli S, Chatelain FC, Bichet D, Lesage F. The family of K channels: salient structural and functional properties. J Physiol. 2014 doi: 10.1113/jphysiol.2014.287268. - DOI - PMC - PubMed

[3] Devilliers M, et al. Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nat Commun. 2013;4:2941. doi: 10.1038/ncomms3941. - DOI - PubMed

[4] Devilliers M, et al. Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nat Commun. 2013;4:2941. doi: 10.1038/ncomms3941. - DOI - PubMed

[5] Vivier D, et al. Development of the first Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K+ Channel 1)-selective agonist possessing in vivo anti-nociceptive activity. Journal of medicinal chemistry. 2017 doi: 10.1021/acs.jmedchem.6b01285. - DOI - PubMed

[6] Vivier D, et al. Development of the first Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K+ Channel 1)-selective agonist possessing in vivo anti-nociceptive activity. Journal of medicinal chemistry. 2017 doi: 10.1021/acs.jmedchem.6b01285. - DOI - PubMed

[7] Brohawn SG, del Marmol J, MacKinnon R. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science. 2012;335:436–441. doi: 10.1126/science.1213808. 335/6067/436 [pii] - DOI - PMC - PubMed

[8] Brohawn SG, del Marmol J, MacKinnon R. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science. 2012;335:436–441. doi: 10.1126/science.1213808. 335/6067/436 [pii] - DOI - PMC - PubMed

[9] Miller AN, Long SB. Crystal structure of the human two-pore domain potassium channel K2P1. Science. 2012;335:432–436. doi: 10.1126/science.1213274. 335/6067/432 [pii] - DOI - PubMed

[10] Miller AN, Long SB. Crystal structure of the human two-pore domain potassium channel K2P1. Science. 2012;335:432–436. doi: 10.1126/science.1213274. 335/6067/432 [pii] - DOI - PubMed

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K_2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site

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K_2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site

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