After an easy win against Bangladesh, England found the Proteas predictably more formidable in Barbados.
The odds, however, are against the Proteas, who have never won a Test series on Australian soil.
Sreesanth then had AB de Villiers caught behind to leave the Proteas struggling at 74-4 at lunch.
Debutant paceman Tanvir Ahmed (4-67) had the Proteas' top order reeling early on as they slipped to 33-3.
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All-rounder Yuvraj injured a wrist in the same game and will miss the two-Test series against the Proteas.
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Clarke played through the pain to score 19 and take 1-29 in Friday's first one-dayer, which the Proteas narrowly won.
Man-of-the-match Johnson wrapped up the Proteas innings for 291 soon after tea.
The dogged batting of Shivnarine Chanderpaul and Dwayne Bravo combined with the Proteas' ineffective attack to produce a soporific start to day four.
The Proteas' preparations for the series, meanwhile, have been thrown into turmoil after the departure of head coach Mickey Arthur earlier this week.
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The Proteas could hardly have wished for a better start to the two-match series, which proceeds their eagerly anticipated tour to Australia in December.
The Proteas lost wickets in each of the first three overs as Australia bounced back from their recent Test series defeat by South Africa.
By that stage the Proteas had 301 on the board and the makings of a comfortable first-innings lead given the attritional nature of the match.
All three missed Sunday's opening one-day loss to the Proteas and are battling to be fit in time for Friday's second match in Cape Town.
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England play the West Indies at The Oval on Monday and the winner of that game will join the Proteas in qualifying for the last four.
Smith opened solidly for the Proteas but the Windies made an early breakthrough when Alviro Petersen (1) miscued a pull of Roach to midwicket at 17-1.
The Proteas went into the match just a point clear at the top of the standings and they will regain the top spot if they win the five-match series.
When the Windies were finally dismissed, skipper Smith and Petersen then batted through the remaining time to carry the Proteas to 23 without loss at the close at Warner Park.
He represented South Africa at the Under-19 World Cup in 2005-06 and it was reported that the Proteas captain Graeme Smith had expressed an interest in wanting Kieswetter for his side.
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Smith, who broke his left hand in the first innings and was also nursing an injured right elbow, batted at number 11 as the Proteas went close to achieving a memorable result.
Australia, who recovered from their 2-0 Test series defeat in India to beat New Zealand by the same margin, play three Tests, followed by two Twenty20 matches and then five one-day internationals against the Proteas.
But with the Proteas relying on pace as their main weapon - and with team management keen to give young star Dale Steyn as much rest as possible - Nel has been brought back in.
But with a number of Australia's star players, including Shane Warne, Glenn McGrath and Adam Gilchrist, having retired in the past couple of years, the Proteas feel they have an excellent opportunity to break their duck.
Clarke is a highly respected figure, as is Australia's coach Mickey Arthur, who as coach of his native South Africa from 2005 to 2010 helped to mold the Proteas into the world-beating side it is today.
Boucher made his Test debut for South Africa in 1997 and went on to score 5, 515 runs and claim a record 555 dismissals for the Proteas before being forced to call time on his international career last month.
When the skipper was out, 67 were needed from 53 balls but then came the flurry of wickets, and with 23 required from the final two overs, Steyn ensured there was to be no first Twenty20 victory for the Tigers against the Proteas.
His brilliant Indian Premier League form continued as he blasted six sixes in his innings, taking the hotly-tipped Proteas to a total of 211-5.
Haddin then lofted Ntini's second delivery with the new ball directly to Proteas debutant JP Duminy.
Proteas keeper Mark Boucher became the first man to reach 500 Test dismissals as the Windies were all out for 546.
"He is the player I respect most, " said Proteas captain Graeme Smith.
Proteas skipper Graeme Smith decided at the last moment not to attempt a shot outside the off-stump, but was unable to withdraw his bat in time and the deflection crashed into the stumps.
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