GHKL domain

Last updated
Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase
PDB 1ah6 EBI.jpg
Structure of the N-terminal domain of the yeast Hsp90 chaperone. [1]
Identifiers
SymbolHATPase_c
Pfam PF02518
InterPro IPR003594
SMART HATPase_c
SCOP2 1ei1 / SCOPe / SUPFAM
CDD cd00075
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1ys3 B:338-445 1ysr B:338-445 1id0 A:374-479

2c2a A:365-479 1i58 A:398-540 1b3q B:398-540 1i5b A:398-540 1i5a B:398-540 1i5d A:398-540 1i5c B:398-540 1i59 B:398-540 1y8n A:236-361 1y8o A:236-361 1y8p A:236-361 1jm6 A:240-363 1gkx A:264-403 1gkz A:264-403 1gjv A:264-403 1nhj A:18-79 1nhi A:18-79 1nhh A:18-79 1b62 A:18-79 1bkn B:20-73 1b63 A:18-79 1h7s A:30-164 1h7u A:30-164 1ea6 B:30-164 1mx0 D:27-179 1mu5 A:27-179 1z5b A:27-179 1z5c B:27-179 1z59 A:27-179 1z5a B:27-179 1thn C:35-136 1tid C:35-136 1l0o A:35-136 1til E:35-136 1th8 A:35-136 1ah6 :26-180 1us7 A:26-180 1amw :26-180 2bre A:26-180 2akp B:26-180 1a4h :26-180 1ah8 A:26-180 2brc A:26-180 1am1 :26-180 1bgq A:26-180 1yc4 A:40-193 1uyg A:40-193 2bt0 A:40-193 1uyc A:40-193 1yer :40-193 1yc3 A:40-193 1uy8 A:40-193 2bz5 A:40-193 1uye A:40-193 2byh A:40-193 1yc1 A:40-193 1uyh A:40-193 1uy9 A:40-193 1uyd A:40-193 1uy6 A:40-193 1uy7 A:40-193 2bsm A:40-193 1yes :40-193 1uyl A:40-193 1uyi A:40-193 2byi A:40-193 1uyf A:40-193 1byq A:40-193 1uyk A:40-193 1osf A:40-193 1yet :40-193 1uym A:35-188 1tc0 B:96-254 1ysz A:96-254 1u2o B:96-254 1yt0 A:96-254 1tbw A:96-254 1qye A:96-254 1u0z A:96-254 1yt2 A:96-254 1tc6 A:96-254 1u0y A:96-254 1qy8 A:96-254 1yt1 A:96-254 1qy5 A:96-254 1y4u B:27-183 1y4s A:27-183 1kij A:28-173 1s16 A:27-172 1s14 B:27-172 1pvg A:55-204 1qzr B:55-204 1zxn C:76-224

Contents

1zxm A:76-224

The GHKL domain (Gyrase, Hsp90, Histidine Kinase, MutL) is an evolutionary conserved protein domain. [2] It is an ATPase domain found in several ATP-binding proteins such as histidine kinase, DNA gyrase B, topoisomerases, [3] heat shock protein HSP90, [4] [5] [6] phytochrome-like ATPases and DNA mismatch repair proteins.

More information about this protein can be found at Protein of the Month: DNA Topoisomerase. [7]

Structure

The fold of this domain consists of two layers, alpha/beta, which contain an 8-stranded mixed beta-sheet. [2]

Subfamilies

InterPro :  IPR020575

InterPro :  IPR032834

Members

Related Research Articles

<span class="mw-page-title-main">Chaperone (protein)</span> Proteins assisting in protein folding

In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.

<span class="mw-page-title-main">Hsp90</span> Heat shock proteins with a molecular mass around 90kDa

Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.

DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-polymerase or by helicase in front of the progressing replication fork. It is the only known enzyme to actively contribute negative supercoiling to DNA, while it also is capable of relaxing positive supercoils. It does so by looping the template to form a crossing, then cutting one of the double helices and passing the other through it before releasing the break, changing the linking number by two in each enzymatic step. This process occurs in bacteria, whose single circular DNA is cut by DNA gyrase and the two ends are then twisted around each other to form supercoils. Gyrase is also found in eukaryotic plastids: it has been found in the apicoplast of the malarial parasite Plasmodium falciparum and in chloroplasts of several plants. Bacterial DNA gyrase is the target of many antibiotics, including nalidixic acid, novobiocin, albicidin, and ciprofloxacin.

<span class="mw-page-title-main">Type II topoisomerase</span> Class of enzymes

Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of ATP, unlike Type I topoisomerase. In this process, these enzymes change the linking number of circular DNA by ±2. Topoisomerases are ubiquitous enzymes, found in all living organisms.

<span class="mw-page-title-main">Heat shock protein 90kDa alpha (cytosolic), member A1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the HSP90AA1 gene.

<span class="mw-page-title-main">CDC37</span> Protein-coding gene in the species Homo sapiens

Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene. This protein is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a HSP90 Co-chaperone with specific function in cell signal transduction. It has been shown to form complex with Hsp90 and a variety of protein kinases including CDK4, CDK6, SRC, RAF1, MOK, as well as eIF-2 alpha kinases. It is thought to play a critical role in directing Hsp90 to its target kinases.

<span class="mw-page-title-main">HSP90AB1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein HSP 90-beta also called HSP90beta is a protein that in humans is encoded by the HSP90AB1 gene.

<span class="mw-page-title-main">PTGES3</span> Protein-coding gene in the species Homo sapiens

Prostaglandin E synthase 3 (cytosolic) is an enzyme that in humans is encoded by the PTGES3 gene.

<span class="mw-page-title-main">AH receptor-interacting protein</span> Protein-coding gene in the species Homo sapiens

AH receptor-interacting protein (AIP) also known as aryl hydrocarbon receptor-interacting protein, immunophilin homolog ARA9, or HBV X-associated protein 2 (XAP-2) is a protein that in humans is encoded by the AIP gene. The protein is a member of the FKBP family.

<span class="mw-page-title-main">ST13</span>

Hsc70-interacting protein also known as suppression of tumorigenicity 13 (ST13) is a protein that in humans is encoded by the ST13 gene.

<span class="mw-page-title-main">BAG2</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 2 is a protein that in humans is encoded by the BAG2 gene.

<span class="mw-page-title-main">TRAP1</span> Protein-coding gene in the species Homo sapiens

Heat shock protein 75 kDa, mitochondrial is a protein that in humans is encoded by the TRAP1 gene.

<span class="mw-page-title-main">TOMM34</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import receptor subunit TOM34 is a protein that in humans is encoded by the TOMM34 gene.

<span class="mw-page-title-main">BAG4</span> Protein-coding gene in the species Homo sapiens

BAG family molecular chaperone regulator 4 is a protein that in humans is encoded by the BAG4 gene.

<span class="mw-page-title-main">ATP5I</span> Protein-coding gene in the species Homo sapiens

ATP synthase subunit e, mitochondrial is an enzyme that in humans is encoded by the ATP5ME gene.

<span class="mw-page-title-main">AHSA1</span> Protein-coding gene in the species Homo sapiens

Activator of 90 kDa heat shock protein ATPase homolog 1 is an enzyme that in humans is encoded by the AHSA1 gene.

AHSA2 also known as AHA1, activator of heat shock 90kDa protein ATPase homolog 2 (yeast) is a human gene which encodes a protein which acts as co-chaperone of Hsp90. AHSA2 and the related AHSA1 belongs to the AHA family of stress-regulated proteins that bind directly to Hsp90 and are required for Hsp90-dependent activation of client proteins.

<span class="mw-page-title-main">Hsp90 inhibitor</span> Drug class

An Hsp90 inhibitor is a substance that inhibits that activity of the Hsp90 heat shock protein. Since Hsp90 stabilizes a variety of proteins required for survival of cancer cells, these substances may have therapeutic benefit in the treatment of various types of malignancies. Furthermore, a number of Hsp90 inhibitors are currently undergoing clinical trials for a variety of cancers. Hsp90 inhibitors include the natural products geldanamycin, Retaspimycin hydrochloride and radicicol as well as semisynthetic derivatives 17-N-Allylamino-17-demethoxygeldanamycin (17AAG).

The chaperone code refers to post-translational modifications of molecular chaperones that control protein folding. Whilst the genetic code specifies how DNA makes proteins, and the histone code regulates histone-DNA interactions, the chaperone code controls how proteins are folded to produce a functional proteome.

<span class="mw-page-title-main">FNIP1</span> Protein-coding gene in the species Homo sapiens

Folliculin-interacting protein 1 (FNIP1) functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 and decelerates its chaperone cycle. FNIP1 acts as a scaffold to load FLCN onto Hsp90. FNIP1 is also involved in chaperoning of both kinase and non-kinase clients.

References

  1. Prodromou C, Roe SM, Piper PW, Pearl LH (June 1997). "A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone". Nat. Struct. Biol. 4 (6): 477–82. doi:10.1038/nsb0697-477. PMID   9187656. S2CID   38764610.
  2. 1 2 Dutta R, Inouye M (January 2000). "GHKL, an emergent ATPase/kinase superfamily". Trends Biochem. Sci. 25 (1): 24–8. doi:10.1016/S0968-0004(99)01503-0. PMID   10637609.
  3. Bellon S, Parsons JD, Wei Y, Hayakawa K, Swenson LL, Charifson PS, Lippke JA, Aldape R, Gross CH (May 2004). "Crystal Structures of Escherichia coli Topoisomerase IV ParE Subunit (24 and 43 Kilodaltons): a Single Residue Dictates Differences in Novobiocin Potency against Topoisomerase IV and DNA Gyrase". Antimicrob. Agents Chemother. 48 (5): 1856–64. doi:10.1128/AAC.48.5.1856-1864.2004. PMC   400558 . PMID   15105144.
  4. Immormino RM, Dollins DE, Shaffer PL, Soldano KL, Walker MA, Gewirth DT (October 2004). "Ligand-induced conformational shift in the N-terminal domain of GRP94, an Hsp90 chaperone". J. Biol. Chem. 279 (44): 46162–71. doi: 10.1074/jbc.M405253200 . PMID   15292259.
  5. Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH (January 2004). "The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37)". Cell. 116 (1): 87–98. doi: 10.1016/S0092-8674(03)01027-4 . PMID   14718169. S2CID   797232.
  6. Wright L, Barril X, Dymock B, Sheridan L, Surgenor A, Beswick M, Drysdale M, Collier A, Massey A, Davies N, Fink A, Fromont C, Aherne W, Boxall K, Sharp S, Workman P, Hubbard RE (June 2004). "Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms". Chem. Biol. 11 (6): 775–85. doi: 10.1016/j.chembiol.2004.03.033 . PMID   15217611.
  7. McDowall J (2006). "DNA Topoisomerase". Protein of the month. InterPro.
This article incorporates text from the public domain Pfam and InterPro: IPR003594