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PDBsum entry 1zcd

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protein Protein-protein interface(s) links
Membrane protein PDB id
1zcd
Jmol
Contents
Protein chains
376 a.a. *
* Residue conservation analysis
PDB id:
1zcd
Name: Membrane protein
Title: Crystal structure of the na+/h+ antiporter nhaa
Structure: Na(+)/h(+) antiporter 1. Chain: a, b. Synonym: sodium/proton antiporter 1. Engineered: yes
Source: Escherichia coli. Organism_taxid: 562. Gene: nhaa. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
3.45Å     R-factor:   0.316     R-free:   0.316
Authors: C.Hunte,E.Screpanti,M.Venturi,A.Rimon,E.Padan,H.Michel
Key ref:
C.Hunte et al. (2005). Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH. Nature, 435, 1197-1202. PubMed id: 15988517 DOI: 10.1038/nature03692
Date:
11-Apr-05     Release date:   05-Jul-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P13738  (NHAA_ECOLI) -  Na(+)/H(+) antiporter NhaA
Seq:
Struc:
388 a.a.
376 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   3 terms 
  Biological process     sodium ion transmembrane transport   8 terms 
  Biochemical function     antiporter activity     3 terms  

 

 
DOI no: 10.1038/nature03692 Nature 435:1197-1202 (2005)
PubMed id: 15988517  
 
 
Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH.
C.Hunte, E.Screpanti, M.Venturi, A.Rimon, E.Padan, H.Michel.
 
  ABSTRACT  
 
The control by Na+/H+ antiporters of sodium/proton concentration and cell volume is crucial for the viability of all cells. Adaptation to high salinity and/or extreme pH in plants and bacteria or in human heart muscles requires the action of Na+/H+ antiporters. Their activity is tightly controlled by pH. Here we present the crystal structure of pH-downregulated NhaA, the main antiporter of Escherichia coli and many enterobacteria. A negatively charged ion funnel opens to the cytoplasm and ends in the middle of the membrane at the putative ion-binding site. There, a unique assembly of two pairs of short helices connected by crossed, extended chains creates a balanced electrostatic environment. We propose that the binding of charged substrates causes an electric imbalance, inducing movements, that permit a rapid alternating-access mechanism. This ion-exchange machinery is regulated by a conformational change elicited by a pH signal perceived at the entry to the cytoplasmic funnel.
 
  Selected figure(s)  
 
Figure 2.
Figure 2: Overall architecture of NhaA. a, Stereo view of a ribbon representation viewed parallel to the membrane (grey broken lines). The 12 TMSs are labelled with roman numerals; they comprise the following residues: 12 -30 (I), 59 -85 (II), 95 -116 (III), 121 -131 (IVp), 134 -143 (IVc), 150 -175 (V), 182 -200 (VI), 205 -218 (VII), 223 -236 (VIII), 247 -271 (IX), 290 -311 (X), 327 -336 (XIc), 340 -350 (XIp) and 357 -382 (XII). N and C indicate the N and C termini. b, TMSs IV/XI assembly. Helices of the assembly and helix V are shown as cylinders, helix X in ribbon representation. The partial charges of the N and C termini of the short helices are indicated. The orientation of the molecule is indicated with respect to a.
Figure 4.
Figure 4: Structural basis of Na^+/H+ translocation and pH regulation. a, Stereo view of TMSs oriented parallel to the membrane, with the cytoplasmic side at the top. The colour code is as in Fig. 2. Residues whose alterations affect pH regulation12,16,31, apparent K[m] (refs 29, 38) or both29,38 are shown with side chains and labelled blue, black and purple, respectively. The putative 'pH sensor' is encircled. The approximate position of the cytoplasmic passage is marked by red dotted lines connecting Asp 164 with residues lining the funnel entry. b, Close interactions between helix IX and helices IVc and XIp that are important for pH regulation. Van der Waals contacts between side chains are indicated with dotted red lines.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2005, 435, 1197-1202) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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PDB codes: 4ain 4doj
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PDB code: 4f35
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PDB codes: 3zux 3zuy
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Structure determination and improved model of plant photosystem I.
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PDB codes: 2wsc 2wse 2wsf 3lw5
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Structure and mechanism of a pentameric formate channel.
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PDB codes: 3kly 3klz
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The mechanism of sodium and substrate release from the binding pocket of vSGLT.
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PDB code: 2xq2
20620041 C.J.Tsai, and C.Ziegler (2010).
Coupling electron cryomicroscopy and X-ray crystallography to understand secondary active transport.
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Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes.
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19923224 K.Herz, A.Rimon, E.Olkhova, L.Kozachkov, and E.Padan (2010).
Transmembrane segment II of NhaA Na+/H+ antiporter lines the cation passage, and Asp65 is critical for pH activation of the antiporter.
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Structural and Functional Analysis of Transmembrane XI of the NHE1 Isoform of the Na+/H+ Exchanger.
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PDB code: 2kbv
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Identification and Characterization of the Na+/H+ Antiporter Nhas3 from the Thylakoid Membrane of Synechocystis sp. PCC 6803.
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Regulation of the Na(+)/H(+) exchanger in the healthy and diseased myocardium.
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The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters.
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19380587 M.D.Slugoski, K.M.Smith, A.M.Ng, S.Y.Yao, E.Karpinski, C.E.Cass, S.A.Baldwin, and J.D.Young (2009).
Conserved Glutamate Residues Glu-343 and Glu-519 Provide Mechanistic Insights into Cation/Nucleoside Cotransport by Human Concentrative Nucleoside Transporter hCNT3.
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19448074 M.Donowitz, S.Mohan, C.X.Zhu, T.E.Chen, R.Lin, B.Cha, N.C.Zachos, R.Murtazina, R.Sarker, and X.Li (2009).
NHE3 regulatory complexes.
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19706416 M.S.Yousef, and L.Guan (2009).
A 3D structure model of the melibiose permease of Escherichia coli represents a distinctive fold for Na+ symporters.
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19924125 N.Reyes, C.Ginter, and O.Boudker (2009).
Transport mechanism of a bacterial homologue of glutamate transporters.
  Nature, 462, 880-885.
PDB code: 3kbc
19171975 P.D.Jeffrey (2009).
Analysis of errors in the structure determination of MsbA.
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19034433 R.Bizzarri, M.Serresi, S.Luin, and F.Beltram (2009).
Green fluorescent protein based pH indicators for in vivo use: a review.
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Functional expression of SCO7832 stimulates tautomycetin production via pathway-specific regulatory gene overexpression in Streptomyces sp. CK4412.
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19679462 S.L.Reichow, and T.Gonen (2009).
Lipid-protein interactions probed by electron crystallography.
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19151209 W.R.Harvey, D.Y.Boudko, M.R.Rheault, and B.A.Okech (2009).
NHE(VNAT): an H+ V-ATPase electrically coupled to a Na+:nutrient amino acid transporter (NAT) forms an Na+/H+ exchanger (NHE).
  J Exp Biol, 212, 347-357.  
19448072 W.R.Harvey (2009).
Voltage coupling of primary H+ V-ATPases to secondary Na+- or K+-dependent transporters.
  J Exp Biol, 212, 1620-1629.  
19478139 X.Gao, F.Lu, L.Zhou, S.Dang, L.Sun, X.Li, J.Wang, and Y.Shi (2009).
Structure and mechanism of an amino acid antiporter.
  Science, 324, 1565-1568.
PDB codes: 3h5m 3h6b 3lrb 3lrc
19389778 Y.Kajiyama, M.Otagiri, J.Sekiguchi, T.Kudo, and S.Kosono (2009).
The MrpA, MrpB and MrpD subunits of the Mrp antiporter complex in Bacillus subtilis contain membrane-embedded and essential acidic residues.
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  18824592 D.Fuster, O.W.Moe, and D.W.Hilgemann (2008).
Steady-state function of the ubiquitous mammalian Na/H exchanger (NHE1) in relation to dimer coupling models with 2Na/2H stoichiometry.
  J Gen Physiol, 132, 465-480.  
18508966 D.G.Fuster, J.Zhang, M.Shi, I.A.Bobulescu, S.Andersson, and O.W.Moe (2008).
Characterization of the sodium/hydrogen exchanger NHA2.
  J Am Soc Nephrol, 19, 1547-1556.  
18321962 D.J.Müller, N.Wu, and K.Palczewski (2008).
Vertebrate membrane proteins: structure, function, and insights from biophysical approaches.
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18707888 E.Padan (2008).
The enlightening encounter between structure and function in the NhaA Na+-H+ antiporter.
  Trends Biochem Sci, 33, 435-443.  
18348129 H.Janovjak, K.T.Sapra, A.Kedrov, and D.J.Müller (2008).
From valleys to ridges: exploring the dynamic energy landscape of single membrane proteins.
  Chemphyschem, 9, 954-966.  
18077454 K.Moncoq, G.Kemp, X.Li, L.Fliegel, and H.S.Young (2008).
Dimeric structure of human Na+/H+ exchanger isoform 1 overproduced in Saccharomyces cerevisiae.
  J Biol Chem, 283, 4145-4154.  
18024499 L.Celik, B.Schiøtt, and E.Tajkhorshid (2008).
Substrate binding and formation of an occluded state in the leucine transporter.
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18647834 L.R.Forrest, Y.W.Zhang, M.T.Jacobs, J.Gesmonde, L.Xie, B.H.Honig, and G.Rudnick (2008).
Mechanism for alternating access in neurotransmitter transporters.
  Proc Natl Acad Sci U S A, 105, 10338-10343.  
18024501 N.Dave, V.A.Lórenz-Fonfría, G.Leblanc, and E.Padrós (2008).
FTIR spectroscopy of secondary-structure reorientation of melibiose permease modulated by substrate binding.
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Common occurrence of internal repeat symmetry in membrane proteins.
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The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport.
  Science, 321, 810-814.
PDB code: 3dh4
18927357 S.Weyand, T.Shimamura, S.Yajima, S.Suzuki, O.Mirza, K.Krusong, E.P.Carpenter, N.G.Rutherford, J.M.Hadden, J.O'Reilly, P.Ma, M.Saidijam, S.G.Patching, R.J.Hope, H.T.Norbertczak, P.C.Roach, S.Iwata, P.J.Henderson, and A.D.Cameron (2008).
Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter.
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PDB codes: 2jln 2jlo
18508767 T.Reddy, J.Ding, X.Li, B.D.Sykes, J.K.Rainey, and L.Fliegel (2008).
Structural and functional characterization of transmembrane segment IX of the NHE1 isoform of the Na+/H+ exchanger.
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PDB code: 2k3c
18411273 Y.Y.Kim, D.Y.Kim, D.Shim, W.Y.Song, J.Lee, J.I.Schroeder, S.Kim, N.Moran, and Y.Lee (2008).
Expression of the novel wheat gene TM20 confers enhanced cadmium tolerance to bakers' yeast.
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Molecular Dynamics Simulations of Na(+)/Cl(-)-Dependent Neurotransmitter Transporters in a Membrane-Aqueous System.
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17704177 D.Hilger, Y.Polyhach, E.Padan, H.Jung, and G.Jeschke (2007).
High-resolution structure of a Na+/H+ antiporter dimer obtained by pulsed electron paramagnetic resonance distance measurements.
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PDB code: 2nq2
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Mechanism of Na+/H+ antiporting.
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Emerging roles of alkali cation/proton exchangers in organellar homeostasis.
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Three two-component transporters with channel-like properties have monovalent cation/proton antiport activity.
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Model structure of the Na+/H+ exchanger 1 (NHE1): functional and clinical implications.
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Emulating membrane protein evolution by rational design.
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18000046 M.Xiang, M.Feng, S.Muend, and R.Rao (2007).
A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension.
  Proc Natl Acad Sci U S A, 104, 18677-18681.  
17493937 S.F.Pedersen, S.A.King, E.B.Nygaard, R.R.Rigor, and P.M.Cala (2007).
NHE1 inhibition by amiloride- and benzoylguanidine-type compounds. Inhibitor binding loci deduced from chimeras of NHE1 homologues with endogenous differences in inhibitor sensitivity.
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Oligomeric states of the SecA and SecYEG core components of the bacterial Sec translocon.
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When biochemistry meets structural biology: the cautionary tale of EmrE.
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17662110 T.Hisamitsu, K.Yamada, T.Y.Nakamura, and S.Wakabayashi (2007).
Functional importance of charged residues within the putative intracellular loops in pH regulation by Na+/ H+ exchanger NHE1.
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17704152 X.Huang, and C.G.Zhan (2007).
How dopamine transporter interacts with dopamine: insights from molecular modeling and simulation.
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Characterizing folding, structure, molecular interactions and ligand gated activation of single sodium/proton antiporters.
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Multiconformation continuum electrostatics analysis of the NhaA Na+/H+ antiporter of Escherichia coli with functional implications.
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16451122 H.Nury, C.Dahout-Gonzalez, V.Trézéguet, G.J.Lauquin, G.Brandolin, and E.Pebay-Peyroula (2006).
Relations between structure and function of the mitochondrial ADP/ATP carrier.
  Annu Rev Biochem, 75, 713-741.  
17071327 I.A.Bobulescu, and O.W.Moe (2006).
Na+/H+ exchangers in renal regulation of acid-base balance.
  Semin Nephrol, 26, 334-344.  
16861220 J.Ding, J.K.Rainey, C.Xu, B.D.Sykes, and L.Fliegel (2006).
Structural and functional characterization of transmembrane segment VII of the Na+/H+ exchanger isoform 1.
  J Biol Chem, 281, 29817-29829.
PDB code: 2htg
16734750 J.F.Lesoine, B.Holmberg, P.Maloney, X.Wang, L.Novotny, and P.A.Knauf (2006).
Development of an spFRET method to measure structure changes in ion exchange proteins.
  Acta Physiol (Oxf), 187, 141-147.  
17056710 L.Bamber, M.Harding, P.J.Butler, and E.R.Kunji (2006).
Yeast mitochondrial ADP/ATP carriers are monomeric in detergents.
  Proc Natl Acad Sci U S A, 103, 16224-16229.  
16446422 L.Guan, I.N.Smirnova, G.Verner, S.Nagamori, S.Nagamoni, and H.R.Kaback (2006).
Manipulating phospholipids for crystallization of a membrane transport protein.
  Proc Natl Acad Sci U S A, 103, 1723-1726.  
17218973 M.E.Malo, and L.Fliegel (2006).
Physiological role and regulation of the Na+/H+ exchanger.
  Can J Physiol Pharmacol, 84, 1081-1095.  
16567631 N.Chai, and P.Bates (2006).
Na+/H+ exchanger type 1 is a receptor for pathogenic subgroup J avian leukosis virus.
  Proc Natl Acad Sci U S A, 103, 5531-5536.  
16814540 R.Dutzler (2006).
The ClC family of chloride channels and transporters.
  Curr Opin Struct Biol, 16, 439-446.  
17146459 S.H.White (2006).
Rhomboid intramembrane protease structures galore!
  Nat Struct Mol Biol, 13, 1049-1051.  
17012318 X.León, R.Lemonnier, G.Leblanc, and E.Padrós (2006).
Changes in secondary structures and acidic side chains of melibiose permease upon cosubstrates binding.
  Biophys J, 91, 4440-4449.  
16785232 X.Ren, D.A.Nicoll, and K.D.Philipson (2006).
Helix packing of the cardiac Na+-Ca2+ exchanger: proximity of transmembrane segments 1, 2, and 6.
  J Biol Chem, 281, 22808-22814.  
16710297 Y.B.Ammar, S.Takeda, T.Hisamitsu, H.Mori, and S.Wakabayashi (2006).
Crystal structure of CHP2 complexed with NHE1-cytosolic region and an implication for pH regulation.
  EMBO J, 25, 2315-2325.
PDB code: 2bec
17008313 Y.W.Zhang, and G.Rudnick (2006).
The cytoplasmic substrate permeation pathway of serotonin transporter.
  J Biol Chem, 281, 36213-36220.  
16216867 A.Karasawa, Y.Tsuboi, H.Inoue, R.Kinoshita, N.Nakamura, and H.Kanazawa (2005).
Detection of oligomerization and conformational changes in the Na+/H+ antiporter from Helicobacter pylori by fluorescence resonance energy transfer.
  J Biol Chem, 280, 41900-41911.  
16277975 E.Padan, E.Bibi, M.Ito, and T.A.Krulwich (2005).
Alkaline pH homeostasis in bacteria: new insights.
  Biochim Biophys Acta, 1717, 67-88.  
16648940 F.Meier-Abt, Y.Mokrab, and K.Mizuguchi (2005).
Organic anion transporting polypeptides of the OATP/SLCO superfamily: identification of new members in nonmammalian species, comparative modeling and a potential transport mode.
  J Membr Biol, 208, 213-227.  
16339740 I.Sobczak, and J.S.Lolkema (2005).
The 2-hydroxycarboxylate transporter family: physiology, structure, and mechanism.
  Microbiol Mol Biol Rev, 69, 665-695.  
16267283 J.Liu, Y.Xue, Q.Wang, Y.Wei, T.H.Swartz, D.B.Hicks, M.Ito, Y.Ma, and T.A.Krulwich (2005).
The activity profile of the NhaD-type Na+(Li+)/H+ antiporter from the soda Lake Haloalkaliphile Alkalimonas amylolytica is adaptive for the extreme environment.
  J Bacteriol, 187, 7589-7595.  
16373573 O.Pornillos, Y.J.Chen, A.P.Chen, and G.Chang (2005).
X-ray structure of the EmrE multidrug transporter in complex with a substrate.
  Science, 310, 1950-1953.
PDB code: 2f2m
16186100 R.Habibian, J.Dzioba, J.Barrett, M.Y.Galperin, P.C.Loewen, and P.Dibrov (2005).
Functional analysis of conserved polar residues in Vc-NhaD, Na+/H+ antiporter of Vibrio cholerae.
  J Biol Chem, 280, 39637-39643.  
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